Next Article in Journal
Musculoskeletal Development and Skeletal Pathophysiology’s
Next Article in Special Issue
Cathepsin K in Pathological Conditions and New Therapeutic and Diagnostic Perspectives
Previous Article in Journal
Oxidative Stress and DNA Damage in Peripheral Blood Mononuclear Cells from Normal, Obese, Prediabetic and Diabetic Persons Exposed to Thyroid Hormone In Vitro
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 16
10.3390/ijms23169089
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Key Role of Lysosomal Protease Cathepsins in Viral Infections

by
Melania Scarcella
1,
Danila d’Angelo
2,
Mariangela Ciampa
1,
Simona Tafuri
2,
Luigi Avallone
2,
Luigi Michele Pavone
1 and
Valeria De Pasquale
2,*
1
Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, Via S. Pansini n. 5, 80131 Naples, Italy
2
Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via Delpino 1, 80137 Naples, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(16), 9089; https://doi.org/10.3390/ijms23169089
Submission received: 21 July 2022 / Revised: 10 August 2022 / Accepted: 12 August 2022 / Published: 13 August 2022
(This article belongs to the Special Issue Lysosomal Proteases and Their Inhibitors)
Browse Figure
Versions Notes

Abstract

:
Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment, cathepsins are also found in the cytoplasm, nucleus, and extracellular space, where they are involved in cell signaling, extracellular matrix assembly/disassembly, and protein processing and trafficking through the plasma and nuclear membrane and between intracellular organelles. Ubiquitously expressed in the body, cathepsins play regulatory roles in a wide range of physiological processes including coagulation, hormone secretion, immune responses, and others. A dysregulation of cathepsin expression and/or activity has been associated with many human diseases, including cancer, diabetes, obesity, cardiovascular and inflammatory diseases, kidney dysfunctions, and neurodegenerative disorders, as well as infectious diseases. In viral infections, cathepsins may promote (1) activation of the viral attachment glycoproteins and entry of the virus into target cells; (2) antigen processing and presentation, enabling the virus to replicate in infected cells; (3) up-regulation and processing of heparanase that facilitates the release of viral progeny and the spread of infection; and (4) activation of cell death that may either favor viral clearance or assist viral propagation. In this review, we report the most relevant findings on the molecular mechanisms underlying cathepsin involvement in viral infection physiopathology, and we discuss the potential of cathepsin inhibitors for therapeutical applications in viral infectious diseases.

1. Classification, Synthesis, Cellular Localization, and Physiopathological Roles of Cathepsin

Cathepsins include a family of lysosomal protases, so-called from the Greek term kathepsein (to digest) to indicate proteases that are active in a slightly acidic environment [1,2,3]. Since the discovery of the first cathepsin in late 1920, to date, more than 20 types of cathepsins have been identified in all living organisms. In humans, cathepsins comprise 15 proteolytic enzymes that are structurally classified on the basis of their catalytic active site residue, namely serine (cathepsin A and G), aspartate (cathepsin D and E), or cysteine (cathepsin B, C, F, H, K, L, O, S, V, X, W, Z). Most of the cathepsins act as endopeptidases, although cathepsins A, B and X may also work as carboxypeptidases and cathepsin H operates as an aminopeptidase [4].
Almost all types of cathepsins are synthesized through a common pathway that starts in the ribosome, with the synthesis of a precursor molecule containing a signal peptide, a precursor peptide, and a catalytic domain. The precursor molecule translocates to the endoplasmic reticulum, where it undergoes the hydrolysis of the signal peptide and progresses to glycosylation. The protein is then transported to the Golgi apparatus where it is further glycosylated and phosphorylated to form a mannose-6-phosphate (M6P) protein, which is specifically recognized by M6P lysosomal receptors, ensuring its transport to the endosomal/lysosomal system [5]. However, some evidence demonstrates the existence of alternative routes for the intracellular transport of the newly synthesized procathepsins that involve lysosomal integral membrane protein (LIMP-2) and sortilin [6]. In the lysosome, the hydrolysis of the precursor protein at a low pH leads to the removal of the prodomain yielding active and mature cathepsin.
The maturation process of procathepsins may occur through either auto processing and self-activation or by other protease catalysis, or through both modes [7,8,9,10,11,12,13,14]. While cathepsins B, H, K, L, and S undergo autoactivation, cathepsins C and X require cathepsins L and S for their activation [7]. On the other hand, cathepsin D maturation proceeds through partial autoactivation and activation by cathepsin B and L [14]. The autocatalytic activation is mediated by glycosaminoglycans (GAGs) [15,16,17], linear negatively charged polysaccharides present in the lysosomes as well as on the cell surface and extracellular matrix (ECM) where they regulate important processes in development, homeostasis, and disease [18,19,20,21]. Procathepsin—GAG interaction triggers a conformational change in the precursor molecule that facilitates processing by another procathepsin molecule [10,16,17,22].
In the endolysosomal compartment, cathepsins carry out the proteolytic processes needed to degrade the cargo transported to the endolysosomes, thus contributing to the protein turnover and the normal metabolism of the cell. In this compartment, cathepsins play a pivotal role in autophagy, regulating the biogenesis and the cellular population of lysosomes and autophagosomes as well as the autophagic flux [8,23,24,25,26]. The involvement of cathepsins in the autophagic pathway is relevant in light of the fundamental role of such a process in neuronal development and degeneration [27,28,29,30]. In addition, cathepsins have been shown to regulate growth and development-related processes through their hydrolytic effect on various hormones and growth factors [3,8,22,28,29,30,31]. In the endosomes of immune cells, they participate in both the innate and adaptative immune responses [32,33,34,35,36]. Deregulation of the expression or activity of cathepsins in the endolysosomes leads to impaired degradation of organelle cargos, resulting in the accumulation of substrates that may be responsible for various pathological conditions [3,8,37,38,39,40,41,42,43,44]. These conditions include lysosomal storage diseases (LSD) such as neuronal ceroid lipofuscinosis [37]; galactosidases [38]; mucopolysaccharidoses [39] and Gaucher disease [40]; Alzheimer’s [41,42]; Parkinson’s and Huntington’s diseases [43]; type I diabetes [44]; auto-immune diseases [3]; and others [8].
Although cathepsins are mainly located in the lysosomes, where they show the highest activity due to the low pH of these organelles, they are also active outside of the endolysosomal compartment (cytosol and extracellular space). It should also be noted that cathepsins can occur, bind, and are catalytic active on the cell surface. Indeed, they can be released in the cytosol through the lysosomal membrane permeabilization induced by a variety of stimuli, such as lysosomotropic agents, oxidative stress, and some cell death effectors [8,45]. In addition to lysosomal membrane permeabilization, other mechanisms may lead to extralysosomal translocation of cathepsins. These mechanisms, which include abnormalities in their biosynthetic machinery, generating cathepsins lacking the signal peptide or truncated cathepsins with modified signal sequences, may direct cathepsin variants to the cytosol as well as to the mitochondria or nucleus. In the cytosol, cathepsins regulate apoptosis by both activating apoptotic proteases and degrading antiapoptotic proteins [2,8,46,47], and mediate inflammatory responses by activating inflammasome [32,33,34,35]. Loss of function or inactivation of cathepsins in the cytosol have been associated with pathological conditions such as neurodegenerative diseases, atherosclerosis [48,49], type 2 diabetes [50,51] kidney diseases [52,53], and ischemia [54,55,56]. In the nucleus, cathepsins are involved in processing transcription factors that regulate the cell cycle, cell proliferation, and differentiation, and therefore, dysregulation of nuclear cathepsins may contribute to the transformed phenotype of cancer cells [57]. Finally, cathepsins are secreted through lysosomal exocytosis or alternative trafficking routes in the extracellular milieu, where they participate in plasma membrane repair, bone remodeling, wound healing, and peptide prohormone processing [8,22]. Extracellular cathepsins are involved in the regulation of extracellular matrix (ECM) remodeling, which plays a fundamental role in the control of cell adhesion, proliferation, polarity, migration, and activation of cell signaling [58,59]. Therefore, cathepsins have been implicated in many diseases such as cancer, tissue fibrosis, osteoarthritis, and other pathological conditions associated with altered ECM homeostasis [8,22]. Figure 1 reports the different localization of cathepsins at distinct cellular compartments and their relative physiological and pathological roles.

2. Aid of Cathepsins to Viruses in the Host Cell Infection

Regardless of their cellular localization, cathepsins have been shown to play an important role in the host cell infection by various types of viruses [60]. Indeed, cathepsins can support the virus’s entry into the target cells, enable virus replication in the infected cells, and promote virus release and spread. Here, the involvement of cathepsins in the physiopathology of viral infections is reported.
Firstly, cathepsins have been shown to strongly affect the infection efficiency of many viruses by modulating their binding to host cell receptors and entry. Indeed, recognition and interaction with cellular receptors is a critical initial step of the viral cell cycle, regulating viral tissue tropism and pathogenesis [61]. The interaction with target cell receptors, which not only serves for attachment but also triggers viral entry and trafficking, is mediated by specific viral proteins expressed on the surface of both enveloped and non-enveloped viruses [62]. In many cases, viral attachment proteins require proteolytic activation by host cell proteases. Cathepsins B and L have been implicated in the proteolytic cleavage of the viral glycoprotein (GP) of the Ebola virus (EBOV) that facilitates virus interaction with the cellular receptor(s) and its entry into target cells [63,64,65]. Interestingly, faster viral fusion kinetics and enhanced infectivity of the Ebola strain named Makona, which carries an A-to-V substitution at position 82 (A82V) in the GP, have been correlated with a more efficient GP processing by cathepsin L [66]. Both cathepsins B and L seem to be also involved in the entry initial step of infection by human papillomavirus type 16 virus (HPV16) [67,68,69]. Furthermore, cathepsins B, L, and S mediating the disassembly of viral particles after endocytosis are required for reovirus entry [70,71,72]. Enzymatic activity of Cathepsin B and L is also utilized by severe acute respiratory syndrome (SARS) coronavirus (CoV) to infect cells expressing angiotensin-converting enzyme 2 (ACE2) receptor [73,74]. Indeed, CoVs, encompassing a large variety of viruses infecting many species of birds and mammals, including humans, employ a diverse array of entry strategies to infect target cells [75]. In particular, CoV entry may occur either via fusion directly at the cell surface or through an endocytic pathway. The spike surface envelope glycoprotein (S), which bears receptor binding and membrane fusion capabilities, is required for viral entry. The S protein is homotrimeric, with each subunit containing the S1 and S2 domains, the former mediating the host receptor binding and the latter required for fusing host and viral membranes [76]. Activation of S protein by proteolytic cleavage is required for viral entry into target cells: cell surface protease activity allows direct membrane fusion, whereas endosomal and lysosomal proteases are involved during endocytosis [77]. In addition to SARS-CoV, the involvement of cathepsins B and L has been demonstrated for Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2, which may exploit both routes of entry depending on the host cells [74,78,79,80,81,82,83,84]. Besides cathepsins B and L, a role for cathepsins K, S, and V in SARS-CoV-2 entry into target cells has also been suggested [85]. Indeed, like other CoVs, to gain entry into target cells, SARS-CoV-2 depends on cleavage and activation of the S protein by host cell proteases that include furin, transmembrane protease serine 2 (TMPRSS2), and cathepsins [80,81,82,83,84,85]. Although the interplay between these host proteases during SARS-CoV-2 infection remains to be fully elucidated, amino acid sequences of the S protein that are susceptible to cleavage by cathepsins and that are highly conserved among all known SARS-CoV-2 variants have been identified [84,85]. In all regions of the spike protein, including the S1/S2 region critical for activation and viral entry, there are amino acid sequences susceptible to cleavage by cathepsins B, K, L, S, and V [85]. Cathepsins not only promote viral infection upon viral entry into target cells, but also activate viral fusion proteins at a late stage of replication. Indeed, cathepsin W activity is required for influenza A virus (IAV) entry at the stage of viral fusion in late endosomes [86]. Furthermore, cathepsins L and B play an important role in promoting the spread of highly pathogenic paramyxoviruses, such as Nipah and Hendra viruses, by converting the viral fusion protein to a mature and fusogenic form in the endosomal compartment [87,88].
Interestingly, cathepsins play a key role in promoting virus release and spread by upregulating and processing the host enzyme Heparanase (HPSE), an endoglycosidase that degrades the glycosaminoglycan heparan sulfate (HS) [89,90,91,92,93,94]. Human HPSE mRNA encodes for a 61.2-kDa protein containing 543 amino acids. Cathepsin L cleaves the proenzyme generating the active form consisting of 8 and 50 kDa subunits that associate noncovalently [95]. Active HPSE is responsible for the degradation of HS chains covalently attached to the extracellular matrix and plasma membrane core proteins forming HS proteoglycans (HSPGs), which are involved in a wide range of physiological functions [96,97,98]. Notably, HSPGs assist viruses in infecting target cells at various steps of their life cycle: they utilize HSPGs for attachment at the cell surface, entry, intracellular trafficking, egress, and spread [94,99,100,101]. Recent evidence demonstrates that host-encoded HPSE is upregulated and required for the release of viral progeny after herpes simplex virus 1 (HSV-1) and 2 (HSV-2) infection [88,90,102,103]. The removal of HS chains by HPSE facilitates the release of the newly made viral particles from the cells and their spread. During the productive phase of HSV-2 infection, the upregulation of HPSE correlated with increased levels of cathepsin L, and the inhibition of either HPSE or the cathepsin resulted to be detrimental to the infection [103]. Similar findings were reported for porcine reproductive and respiratory syndrome virus (PRRSV) whose infection causes upregulation of cathepsin L and heparanase, leading to a decrease of cell surface HS chains and, in turn, promoting viral release [104]. In addition, upregulation of cathepsin L and HPSE is involved in the pathogenesis of Dengue virus (DENV) infection [105,106]. Roles in the virus release and spread for cathepsins and HPSE have also been demonstrated in HPV16 [107], respiratory syncytial virus (RSV) [108], and hepatitis C virus (HCV) [109], as well as some CoVs and SARS-CoV2 infections [94,110,111,112].
A relevant aspect of cathepsin involvement in viral infections is their roles in antigen processing and presentation (host adaptative immune response) and activation of toll-like receptors (innate immune response) [113,114,115,116,117,118]. Indeed, cathepsins are known to degrade endocytosed and endogenous antigens to antigen peptides that bind to the major histocompatibility (MHC) class II molecules [113,114,115,116,119]. On the other hand, viruses exploit multiple mechanisms to evade immune recognition, including the manipulation of host antigen processing and presentation mechanisms [120]. This strategy to escape immune response enables the viruses to efficiently replicate in the infected cells. One example is provided by the ectromelia virus, which suppresses the expression of cathepsins B, L, and S in conventional dendritic cells to avoid host immune response and productively replicate [121]. Furthermore, cathepsins B, C, S, and Z were found to be downregulated in dendritic cells infected by human immunodeficiency virus type 1 (HIV-1), resulting in enhanced virus replication and transfer to contacting T lymphocytes, but decreased HIV-1 antigen processing and presentation to these T cells [122]. Increased levels of cathepsin B associated with impaired MHC class II antigen-processing pathways were found in IAV infection in vitro and in vivo [123]. Indeed, in IAV infection, cathepsin B has also been involved in progeny virion production [124]. By contrast, decreased expression levels of cathepsin S associated with an impairment of MHC class II maturation were observed in dendritic cells exposed to HCV or in hepatocytes expressing HCV proteins [125]. In SARS-CoV-infected monocytes, downregulation of the expression of cathepsins A, S, and H involved in antigen presentation and processing was found, suggesting a limited activation of a favorable adaptive immune response against this virus [126].
In addition, some viruses have developed strategies to evade the host innate immune response that involve the activation of various pattern recognition receptors (PRRs), including toll-like receptors (TLRs), among others, and the subsequent signaling resulting in the production of proinflammatory cytokines and/or the activation of programmed cell death [114,117,118,120,127,128,129]. For example, IAV is recognized by various PRRs, depending on the cellular compartment, the different types of cells, and the different stages of infection [130], and may also trigger PRR activation mechanisms to subvert the innate immune response [131,132]. Indeed, TRL activation leading to autophagy and apoptosis is subverted by IAV to enhance virion stability [133,134,135] and to facilitate its replication [136]. Activation of RIG-I-like receptors by RSV infection is associated with the overexpression of cathepsins B, C, E, G, H, K, L, S, W, and Z in infected mouse airways [118]. In HBV infection, impairment of autophagy correlated to an accumulation of immature lysosomes in infected cells has been demonstrated. The analyses of clinical specimens from chronic HBV-infected patients showed enhanced levels of cathepsin D in the liver tissues [137]. Cathepsin B acts as an upstream activator of the intrinsic apoptotic pathway that is exploited by noroviruses to expand the window time of their replication [138]. Both cathepsins B and S have been shown to contribute to apoptosis via caspase activation in DENV infection [139]. Furthermore, cathepsin B has been shown to exacerbate coxsackievirus B3-induced myocarditis in mice through activating inflammasome and promoting pyroptosis, a type of programmed cell death [140]. Interestingly, highly pathogenic human CoVs, including SARS-CoV, MERS-CoV, and SARS-CoV-2, besides suppressing interferon-mediated antiviral response, trigger massive cell death and cytopathy that release a large number of virion particles, thus facilitating viral dissemination [141]. In particular, transcriptomic analysis of peripheral blood mononuclear cells from COVID-19 patients demonstrated a remarkable increase of cathepsins B and L associated with the apoptotic pathway [142]. However, cathepsin activity may also contribute to the antiviral immune response by reducing viral replication. This is the case for cathepsin C, which has been shown to limit acute cytomegalovirus (CMV) infection in mice [143]. Table 1 summarizes the diverse roles of distinct cathepsins in the human infectious diseases caused by viruses.

3. Cathepsins as Potential Targets for Antiviral Therapies

Targeting cathepsins has proven to be a valid strategy for the development of effective antiviral drugs. A comprehensive list of cathepsin inhibitors is present in the MEROPS database (http://www.ebi.ac.uk/merops/, accessed on 20 July 2022) [144]. Furthermore, an elegant review by Pišlar and coworkers [74] reports an updated list of cathepsin inhibitors tested for Cov inhibition, including SARS-CoV-2, while a review by Liu and co-workers [145] nicely describes the antiviral properties, pharmacology, and toxicity of seven cathepsin L selective inhibitors that may represent an effective therapeutic option for COVID-19. Due to the diverse roles of cathepsins in promoting viral infections, different cathepsin-mediated pathways can be targeted to effectively fight the propagation and transmission of viruses. Herein, we report some examples of specific cathepsin inhibitors and their mechanisms of antiviral action.
In order to block cathepsin-mediated host cell entry and, in particular, the endosomal proteolysis step of entry, the cysteine protease inhibitor K11777, (2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl] amino}-3-phenylpropanamide) and closely related vinylsulfones were developed, proving particularly effective for the treatment of filoviruses, such as EBOV and some paramyxoviruses [146]. The cysteine protease inhibitor K11777 has also been shown to inhibit CoV infection, but only in cell lines lacking activating serine proteases. In target cells expressing cell surface serine protease, only the use of both K11777 and a serine protease inhibitor such as camostat showed antiviral activity in an in vivo animal model of SARS-CoV infection [146]. The combined use of camostat or other serine protease inhibitors targeting TMPRSS2 and cathepsin inhibitor apilimod has been proven to strongly block SARS-CoV-2 infection in different cell types [147,148,149]. However, apilimod has been shown to dampen host immune response against SARS-CoV-2, leading to the exacerbation of the already impaired T cell immunity in affected patients, thus suggesting caution in its application [150]. Among the small molecules targeting cathepsins B and/or L, MDL 28170 (carbobenzoxy-valyl-phenylalanial; Z-Val-Phe-CHO) has been shown to impair infection by SARS-CoV-1 and EBOV and is under clinical study for use in COVID-19 [148,151,152], Z LVG CHN2 (N-benzyloxycarbonyl-leucyl-valyl-glycine diazomethylketone) strongly suppresses HSV replication [153] and inhibits the entry step of MERS and SARS-CoV-2 [148,154], and ONO 5334 (N-[(1S)-3-[(2Z)-2-[(4R)-3,4-dimethyl-1,3-thiazolidin-2-ylidene]hydrazinyl]-1-(oxan-4-yl)-2,3-dioxopropyl]cycloheptanecarboxamide) is a cathepsin K inhibitor that impairs the proper processing of SARS-CoV-2 S protein within the endosome, thus inhibiting its fusogenic properties [148].
In addition, the effective and selective inhibitory activity against cathepsin B and/or cathepsin L of a variety of natural products emerged as useful antiviral therapeutics targeting viral entry pathways [155,156,157,158,159]. The most studied commercially available natural cathepsin inhibitor is E-64 (L-trans-Epoxysuccinyl-leucylamido (4-guanidino) butane), isolated from the fungus Aspergillus japonicus, which has the advantages of high potency and low toxicity [160]. It has been shown to inhibit the disassembly of reovirus virions after endocytosis [161], prevent upregulation of cathepsins and enhance viral clearance in RSV-infected lungs [118], and block MERS-CoV and SARS-CoV at the entry stage [162]. Other natural cathepsin antagonists include the linear lipopeptide gallinamide A [163], isolated from a Schizothrix sp. cyanobacterium, which selectively inhibits cathepsin L, as well as tokaramide A and miraziridine A [164,165], isolated from the marine sponge Theonella aff. mirabilis and aloperine, a component of the seeds and leaves of Sophora alopecuroid, which are selective inhibitors of cathepsin B [156]. In particular, the marine natural product gallinamide A potently inhibits SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range [166]. The quinolizidine-type alkaloid aloperine was shown to inhibit HIV-1 entry into cells by blocking the virus from fusion with the host cell membrane [167], to prevent HCV propagation in primary human hepatocytes and block HCV cell-to-cell viral transmission [168]. Aloperine derivatives were obtained with enhanced antiviral activity towards IAV [169] and high anti-EBOV and anti-Marburg virus activity both in vitro and in vivo [156]. A schematic list of the above described cathepsin inhibitors is reported in Table 2.
Selective cathepsin inhibitors have been extensively used in basic and translational research, allowing a better understanding of the pathogenesis of the infectious diseases caused by viruses and providing valuable information for the development of antiviral drugs and vaccines. It is notable that several cathepsin inhibitors are already successfully employed in clinical practice for the treatment of some viral infections [170].

4. Conclusions

Cathepsins are a group of proteolytic enzymes with a broad spectrum of substrates and multiple functions at different locations inside and outside of the cells. In addition to their primary physiological roles in protein turnover and normal cellular metabolism, cathepsins fulfill many additional functions essential for cellular homeostasis: they participate in both the innate and adaptative immune responses, such as antigen presentation and TLR activation, hormone and growth factor processing, autophagy, apoptosis and necroptosis, and inflammation, as well as the processing of transcription factors involved in cell proliferation and differentiation. Altered expression and/or functional profiles of cathepsins have been found in a wide range of pathological states, thus making them potential biomarkers and/or therapeutic targets for many diseases. Here, we have focused on the involvement of cathepsins in the pathogenesis of viral infections. The life cycle of a virus in a host cell includes viral determinants attachment to cell surface factors and/or receptors, entry by either endocytosis or membrane fusion mechanisms, intracellular trafficking, replication and transcription of the viral genome, assembly of newly made virion particles, and egress to infect neighboring cells, thus propagating the infection. In addition, to ensure the replication and spread of the infection through the host organism, pathogenic viruses have developed several strategies to hijack host defenses, including the impairment of immune responses, the manipulation of apoptosis, the modulation of metabolism, modification of the redox environment, and others. Interestingly, robust evidence has demonstrated the involvement of cathepsins in both processes by which viruses infect the host organism and escape the host defenses. In this review, some representative examples of the molecular mechanisms by which cathepsins support the interactions of viruses with target cells at different steps of their life cycle have been reported.
Due to the emergence of infectious diseases that cause pandemics and therefore pose a serious threat to public health and global stability, many research efforts have been focused on the development of effective antiviral drugs. These include several selective cathepsin inhibitors, some of which have been repurposed to combat the new emergence of COVID-19. Thus, here we have also reported some examples and applications of the incredible variety of cathepsin inhibitors developed to date for the treatment of various infectious diseases that represent promising wide-spectrum antiviral agents.

Author Contributions

Conceptualization, M.S., V.D.P. and L.M.P.; writing—original draft preparation, M.S., D.d., M.C., S.T., L.A., L.M.P. and V.D.P.; writing—review and editing, M.S., L.M.P. and V.D.P.; supervision, L.M.P. and V.D.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

We apologize to all the authors whose work could not be cited due to space limitations.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Schröder, B.A.; Wrocklage, C.; Hasilik, A.; Saftig, P. The proteome of lysosomes. Proteomics 2010, 10, 4053–4076. [Google Scholar] [CrossRef] [PubMed]
  2. Turk, V.; Stoka, V.; Vasiljeva, O.; Renko, M.; Sun, T.; Turk, B.; Turk, D. Cysteine cathepsins: From structure, function and regulation to new frontiers. Biochim. Biophys. Acta BBA-Proteins Proteom. 2012, 1824, 68–88. [Google Scholar] [CrossRef] [PubMed]
  3. Patel, S.; Homaei, A.; El-Seedi, H.R.; Akhtar, N. Cathepsins: Proteases that are vital for survival but can also be fatal. Biomed. Pharmacother. 2018, 105, 526–532. [Google Scholar] [CrossRef] [PubMed]
  4. Rawlings, N.D.; Barrett, A.J.; Finn, R. Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2016, 44, D343–D350. [Google Scholar] [CrossRef]
  5. Braulke, T.; Bonifacino, J.S. Sorting of lysosomal proteins. Biochim. Biophys. Acta 2009, 1793, 605–614. [Google Scholar] [CrossRef]
  6. Coutinho, M.F.; Prata, M.J.; Alves, S. A shortcut to the lysosome: The mannose-6-phosphate-independent pathway. Mol. Genet. Metab. 2012, 107, 257–266. [Google Scholar] [CrossRef]
  7. Verma, S.; Dixit, R.; Pandey, K.C. Cysteine Proteases: Modes of Activation and Future Prospects as Pharmacological Targets. Front. Pharmacol. 2016, 7, 107. [Google Scholar] [CrossRef]
  8. Yadati, T.; Houben, T.; Bitorina, A.; Shiri-Sverdlov, R. The Ins and Outs of Cathepsins: Physiological Function and Role in Disease Management. Cells 2020, 9, 1679. [Google Scholar] [CrossRef]
  9. Wittlin, S.; Rosel, J.; Hofmann, F.; Stover, D.R. Mechanisms and kinetics of procathepsin D activation. JBIC J. Biol. Inorg. Chem. 1999, 265, 384–393. [Google Scholar] [CrossRef]
  10. Vasiljeva, O.; Dolinar, M.; Pungerčar, J.R.; Turk, V.; Turk, B. Recombinant human procathepsin S is capable of autocatalytic processing at neutral pH in the presence of glycosaminoglycans. FEBS Lett. 2005, 579, 1285–1290. [Google Scholar] [CrossRef]
  11. Pungerčar, J.R.; Caglič, D.; Sajid, M.; Dolinar, M.; Vasiljeva, O.; Požgan, U.; Turk, D.; Bogyo, M.; Turk, V.; Turk, B. Autocatalytic processing of procathepsin B is triggered by proenzyme activity. FEBS J. 2009, 276, 660–668. [Google Scholar] [CrossRef]
  12. Collette, J.; Bocock, J.P.; Ahn, K.; Chapman, R.L.; Godbold, G.; Yeyeodu, S.; Erickson, A.H. Biosynthesis and Alternate Targeting of the Lysosomal Cysteine Protease Cathepsin L. Int. Rev. Cytol. 2004, 241, 1–51. [Google Scholar] [CrossRef]
  13. Rojnik, M.; Jevnikar, Z.R.; Doljak, B.; Turk, S.; Zidar, N.; Kos, J. The influence of differential processing of procathepsin H on its aminopeptidase activity, secretion and subcellular localization in human cell lines. Eur. J. Cell Biol. 2012, 91, 757–764. [Google Scholar] [CrossRef]
  14. Laurent-Matha, V.; Derocq, D.; Prébois, C.; Katunuma, N.; Liaudet-Coopman, E. Processing of Human Cathepsin D Is Independent of Its Catalytic Function and Auto-Activation: Involvement of Cathepsins L and B. J. Biochem. 2006, 139, 363–371. [Google Scholar] [CrossRef]
  15. Fairhead, M.; Kelly, S.M.; van der Walle, C.F. A heparin binding motif on the pro-domain of human procathepsin L mediates zymogen destabilization and activation. Biochem. Biophys. Res. Commun. 2008, 366, 862–867. [Google Scholar] [CrossRef]
  16. Caglič, D.; Pungerčar, J.R.; Pejler, G.; Turk, V.; Turk, B. Glycosaminoglycans Facilitate Procathepsin B Activation through Disruption of Propeptide-Mature Enzyme Interactions. J. Biol. Chem. 2007, 282, 33076–33085. [Google Scholar] [CrossRef]
  17. Bojarski, K.K.; Karczyńska, A.S.; Samsonov, S.A. Role of Glycosaminoglycans in Procathepsin B Maturation: Molecular Mechanism Elucidated by a Computational Study. J. Chem. Inf. Model. 2020, 60, 2247–2256. [Google Scholar] [CrossRef]
  18. Ricard-Blum, S.; Lisacek, F. Glycosaminoglycanomics: Where we are. Glycoconj. J. 2017, 34, 339–349. [Google Scholar] [CrossRef]
  19. Kjellén, L.; Lindahl, U. Specificity of glycosaminoglycan–protein interactions. Curr. Opin. Struct. Biol. 2018, 50, 101–108. [Google Scholar] [CrossRef]
  20. De Pasquale, V.; Pavone, L.M. Heparan sulfate proteoglycans: The sweet side of development turns sour in mucopolysaccharidoses. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2019, 1865, 165539. [Google Scholar] [CrossRef]
  21. Shi, D.; Sheng, A.; Chi, L. Glycosaminoglycan-Protein Interactions and Their Roles in Human Disease. Front. Mol. Biosci. 2021, 8, 639666. [Google Scholar] [CrossRef]
  22. Vidak, E.; Javoršek, U.; Vizovišek, M.; Turk, B. Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment. Cells 2019, 8, 264. [Google Scholar] [CrossRef]
  23. Dennemärker, J.; Lohmüller, T.; Müller, S.; Aguilar, S.V.; Tobin, D.J.; Peters, C.; Reinheckel, T. Impaired turnover of autophagolysosomes in cathepsin L deficiency. Biol. Chem. 2010, 391, 913–922. [Google Scholar] [CrossRef]
  24. Müller, S.; Dennemärker, J.; Reinheckel, T. Specific functions of lysosomal proteases in endocytic and autophagic pathways. Biochim. Biophys. Acta (BBA)-Proteins Proteom. 2012, 1824, 34–43. [Google Scholar] [CrossRef]
  25. Man, S.M.; Kanneganti, T.-D. Regulation of lysosomal dynamics and autophagy by CTSB/cathepsin B. Autophagy 2016, 12, 2504–2505. [Google Scholar] [CrossRef]
  26. Yang, M.; Liu, J.; Shao, J.; Qin, Y.; Ji, Q.; Zhang, X.; Du, J. Cathepsin S-mediated autophagic flux in tumor-associated macrophages accelerate tumor development by promoting M2 polarization. Mol. Cancer 2014, 13, 43. [Google Scholar] [CrossRef]
  27. Bárány, I.; Berenguer, E.; Solís, M.-T.; Pérez-Pérez, Y.; Santamaria, M.E.; Crespo, J.L.; Risueño, M.C.; Díaz, I.; Testillano, P.S. Autophagy is activated and involved in cell death with participation of cathepsins during stress-induced microspore embryogenesis in barley. J. Exp. Bot. 2018, 69, 1387–1402. [Google Scholar] [CrossRef]
  28. Winckler, B.; Faundez, V.; Maday, S.; Cai, Q.; Almeida, C.G.; Zhang, H. The Endolysosomal System and Proteostasis: From Development to Degeneration. J. Neurosci. 2018, 38, 9364–9374. [Google Scholar] [CrossRef]
  29. Andres-Alonso, M.; Kreutz, M.R.; Karpova, A. Autophagy and the endolysosomal system in presynaptic function. Cell Mol. Life Sci. 2020, 78, 2621–2639. [Google Scholar] [CrossRef]
  30. Hsu, A.; Podvin, S.; Hook, V. Lysosomal Cathepsin Protease Gene Expression Profiles in the Human Brain During Normal Development. J. Mol. Neurosci. 2018, 65, 420–431. [Google Scholar] [CrossRef]
  31. Authier, F.; Kouach, M.; Briand, G. Endosomal proteolysis of insulin-like growth factor-I at its C-terminal D-domain by cathepsin B. FEBS Lett. 2005, 579, 4309–4316. [Google Scholar] [CrossRef] [PubMed]
  32. Palesch, D.; Wagner, J.; Meid, A.; Molenda, N.; Sienczyk, M.; Burkhardt, J.; Münch, J.; Prokop, L.; Stevanovic, S.; Westhoff, M.-A.; et al. Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells. Cancer Immunol. Immunother. 2016, 65, 283–291. [Google Scholar] [CrossRef] [PubMed]
  33. Yan, X.; Wu, Z.; Wang, B.; Yu, T.; Hu, Y.; Wang, S.; Deng, C.; Zhao, B.; Nakanishi, H.; Zhang, X. Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis. Evid.-Based Complement. Altern. Med. 2020, 2020, 4517587. [Google Scholar] [CrossRef] [PubMed]
  34. Nanut, M.P.; Fonović, U.P.; Jakoš, T.; Kos, J. The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function. Front. Immunol. 2021, 12, 680279. [Google Scholar] [CrossRef] [PubMed]
  35. Campden, R.I.; Zhang, Y. The role of lysosomal cysteine cathepsins in NLRP3 inflammasome activation. Arch. Biochem. Biophys. 2019, 670, 32–42. [Google Scholar] [CrossRef] [PubMed]
  36. Creasy, B.M.; McCoy, K.L. Cytokines regulate cysteine cathepsins during TLR responses. Cell. Immunol. 2011, 267, 56–66. [Google Scholar] [CrossRef] [PubMed]
  37. Ketterer, S.; Gomez-Auli, A.; Hillebrand, L.E.; Petrera, A.; Ketscher, A.; Reinheckel, T. Inherited diseases caused by mutations in cathepsin protease genes. FEBS J. 2017, 284, 1437–1454. [Google Scholar] [CrossRef] [PubMed]
  38. Timur, Z.K.; Demir, S.A.; Seyrantepe, V. Lysosomal Cathepsin a Plays a Significant Role in the Processing of Endogenous Bioactive Peptides. Front. Mol. Biosci. 2016, 3, 68. [Google Scholar] [CrossRef]
  39. De Pasquale, V.; Moles, A.; Pavone, L.M. Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy. Cells 2020, 9, 979. [Google Scholar] [CrossRef]
  40. Afinogenova, Y.; Ruan, J.; Yang, R.; Kleytman, N.; Pastores, G.; Lischuk, A.; Mistry, P.K. Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease. Mol. Genet. Metab. 2019, 128, 62–67. [Google Scholar] [CrossRef]
  41. Hook, V.; Funkelstein, L.; Wegrzyn, J.; Bark, S.; Kindy, M.; Hook, G. Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer’s disease. Biochim. Biophys. Acta (BBA)-Proteins Proteom. 2012, 1824, 89–104. [Google Scholar] [CrossRef]
  42. Hook, V.; Yoon, M.; Mosier, C.; Ito, G.; Podvin, S.; Head, B.P.; Rissman, R.; O’Donoghue, A.J.; Hook, G. Cathepsin B in neurodegeneration of Alzheimer’s disease, traumatic brain injury, and related brain disorders. Biochim. Biophys. Acta (BBA)-Proteins Proteom. 2020, 1868, 140428. [Google Scholar] [CrossRef]
  43. Drobny, A.; Huarcaya, S.P.; Dobert, J.; Kluge, A.; Bunk, J.; Schlothauer, T.; Zunke, F. The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches. Biochim. Biophys. Acta Mol. Cell Res. 2022, 1869, 119243. [Google Scholar] [CrossRef]
  44. Hsing, L.C.; Kirk, E.A.; McMillen, T.S.; Hsiao, S.-H.; Caldwell, M.; Houston, B.; Rudensky, A.Y.; LeBoeuf, R.C. Roles for cathepsins S, L, and B in insulitis and diabetes in the NOD mouse. J. Autoimmun. 2010, 34, 96–104. [Google Scholar] [CrossRef]
  45. Oberle, C.; Huai, J.; Reinheckel, T.; Tacke, M.; Rassner, M.; Ekert, P.; Buellesbach, J.; Borner, C. Lysosomal membrane permeabilization and cathepsin release is a Bax/Bak-dependent, amplifying event of apoptosis in fibroblasts and monocytes. Cell Death Differ. 2010, 17, 1167–1178. [Google Scholar] [CrossRef]
  46. Stoka, V.; Turk, V.; Turk, B. Lysosomal cysteine cathepsins: Signaling pathways in apoptosis. Biol. Chem. 2007, 388, 555–560. [Google Scholar] [CrossRef]
  47. Kavčič, N.; Butinar, M.; Sobotič, B.; Česen, M.H.; Petelin, A.; Bojić, L.; Bergant, T.Z.; Bratovš, A.; Reinheckel, T.; Turk, B. Intracellular cathepsin C levels determine sensitivity of cells to leucyl-leucine methyl ester-triggered apoptosis. FEBS J. 2020, 287, 5148–5166. [Google Scholar] [CrossRef]
  48. Stoka, V.; Turk, V.; Turk, B. Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res. Rev. 2016, 32, 22–37. [Google Scholar] [CrossRef]
  49. Lowry, J.R.; Klegeris, A. Emerging roles of microglial cathepsins in neurodegenerative disease. Brain Res. Bull. 2018, 139, 144–156. [Google Scholar] [CrossRef]
  50. Ding, L.; Houben, T.; Oligschlaeger, Y.; Bitorina, A.V.; Verwer, B.J.; Tushuizen, M.E.; Shiri-Sverdlov, R. Plasma Cathepsin D Activity Rather Than Levels Correlates with Metabolic Parameters of Type 2 Diabetes in Male Individuals. Front. Endocrinol. 2020, 11, 575070. [Google Scholar] [CrossRef]
  51. Liu, L.; Chen, B.; Zhang, X.; Tan, L.; Wang, D.W. Increased Cathepsin D Correlates with Clinical Parameters in Newly Diagnosed Type 2 Diabetes. Dis. Mark. 2017, 2017, 5286408. [Google Scholar] [CrossRef]
  52. Cocchiaro, P.; De Pasquale, V.; Della Morte, R.; Tafuri, S.; Avallone, L.; Pizard, A.; Moles, A.; Pavone, L.M. The Multifaceted Role of the Lysosomal Protease Cathepsins in Kidney Disease. Front. Cell Dev. Biol. 2017, 5, 114. [Google Scholar] [CrossRef]
  53. Cocchiaro, P.; Fox, C.; Tregidgo, N.W.; Howarth, R.; Wood, K.M.; Situmorang, G.; Pavone, L.M.; Sheerin, N.S.; Moles, A. Lysosomal protease cathepsin D; a new driver of apoptosis during acute kidney injury. Sci. Rep. 2016, 6, 27112. [Google Scholar] [CrossRef]
  54. Xu, M.; Yang, L.; Rong, J.-G.; Ni, Y.; Gu, W.-W.; Luo, Y.; Ishidoh, K.; Katunuma, N.; Li, Z.-S.; Zhang, H.-L. Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid-mitochondrial apoptotic signaling pathway. Glia 2014, 62, 855–880. [Google Scholar] [CrossRef]
  55. Xu, W.; Yu, C.; Piao, L.; Inoue, A.; Wang, H.; Meng, X.; Li, X.; Cui, L.; Umegaki, H.; Shi, G.-P.; et al. Cathepsin S-Mediated Negative Regulation of Wnt5a/SC35 Activation Contributes to Ischemia-Induced Neovascularization in Aged Mice. Circ. J. 2019, 83, 2537–2546. [Google Scholar] [CrossRef]
  56. Peng, K.; Liu, H.; Yan, B.; Meng, X.; Song, S.; Ji, F.; Xia, Z. Inhibition of cathepsin S attenuates myocardial ischemia/reperfusion injury by suppressing inflammation and apoptosis. J. Cell. Physiol. 2021, 236, 1309–1320. [Google Scholar] [CrossRef]
  57. Soond, S.M.; Kozhevnikova, M.V.; Frolova, A.S.; Savvateeva, L.V.; Plotnikov, E.Y.; Townsend, P.A.; Han, Y.-P.; Zamyatnin, A.A. Lost or Forgotten: The nuclear cathepsin protein isoforms in cancer. Cancer Lett. 2019, 462, 43–50. [Google Scholar] [CrossRef]
  58. Manou, D.; Caon, I.; Bouris, P.; Triantaphyllidou, I.-E.; Giaroni, C.; Passi, A.; Karamanos, N.K.; Vigetti, D.; Theocharis, A.D. The Complex Interplay Between Extracellular Matrix and Cells in Tissues. Methods Mol. Biol. 2019, 1952, 1–20. [Google Scholar] [CrossRef]
  59. Vizovišek, M.; Fonović, M.; Turk, B. Cysteine cathepsins in extracellular matrix remodeling: Extracellular matrix degradation and beyond. Matrix Biol. 2019, 75–76, 141–159. [Google Scholar] [CrossRef]
  60. Brix, K. Host Cell Proteases: Cathepsins. In Activation of Viruses by Host Proteases; Springer: Cham, Switzerland, 2018; pp. 249–276. [Google Scholar] [CrossRef]
  61. Maginnis, M.S. Virus-Receptor Interactions: The Key to Cellular Invasion. J. Mol. Biol. 2018, 430, 2590–2611. [Google Scholar] [CrossRef]
  62. Grove, J.; Marsh, M. The cell biology of receptor-mediated virus entry. J. Cell Biol. 2011, 195, 1071–1082. [Google Scholar] [CrossRef] [PubMed]
  63. Schornberg, K.; Matsuyama, S.; Kabsch, K.; Delos, S.; Bouton, A.; White, J. Role of Endosomal Cathepsins in Entry Mediated by the Ebola Virus Glycoprotein. J. Virol. 2006, 80, 4174–4178. [Google Scholar] [CrossRef] [PubMed]
  64. Kaletsky, R.L.; Simmons, G.; Bates, P. Proteolysis of the Ebola Virus Glycoproteins Enhances Virus Binding and Infectivity. J. Virol. 2007, 81, 13378–13384. [Google Scholar] [CrossRef] [PubMed]
  65. Yamaoka, S.; Ebihara, H. Pathogenicity and Virulence of Ebolaviruses with Species- and Variant-specificity. Virulence 2021, 12, 885–901. [Google Scholar] [CrossRef] [PubMed]
  66. Fels, J.M.; Bortz, R.H.; Alkutkar, T.; Mittler, E.; Jangra, R.K.; Spence, J.S.; Chandran, K. A Glycoprotein Mutation That Emerged during the 2013–2016 Ebola Virus Epidemic Alters Proteolysis and Accelerates Membrane Fusion. mBio 2021, 12, e03616-20. [Google Scholar] [CrossRef] [PubMed]
  67. Dabydeen, S.A.; Meneses, P.I. The role of NH4Cl and cysteine proteases in Human Papillomavirus type 16 infection. Virol. J. 2009, 6, 109–112. [Google Scholar] [CrossRef] [PubMed]
  68. Calton, C.M.; Schlegel, A.; Chapman, J.A.; Campos, S. Human papillomavirus type 16 does not require cathepsin L or B for infection. J. Gen. Virol. 2013, 94, 1865–1869. [Google Scholar] [CrossRef]
  69. Cerqueira, C.; Ventayol, P.S.; Vogeley, C.; Schelhaas, M. Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space to Facilitate Entry into Host Cells. J. Virol. 2015, 89, 7038–7052. [Google Scholar] [CrossRef]
  70. Ebert, D.H.; Deussing, J.; Peters, C.; Dermody, T.S. Cathepsin L and Cathepsin B Mediate Reovirus Disassembly in Murine Fibroblast Cells. J. Biol. Chem. 2002, 277, 24609–24617. [Google Scholar] [CrossRef]
  71. Golden, J.W.; Bahe, J.A.; Lucas, W.T.; Nibert, M.L.; Schiff, L.A. Cathepsin S Supports Acid-independent Infection by Some Reoviruses. J. Biol. Chem. 2004, 279, 8547–8557. [Google Scholar] [CrossRef]
  72. Mainou, B.A. The Orchestra of Reovirus Cell Entry. Curr. Clin. Microbiol. Rep. 2017, 4, 142–149. [Google Scholar] [CrossRef]
  73. Huang, I.-C.; Bosch, B.J.; Li, F.; Li, W.; Lee, K.H.; Ghiran, S.; Vasilieva, N.; Dermody, T.S.; Harrison, S.C.; Dormitzer, P.R.; et al. SARS Coronavirus, but Not Human Coronavirus NL63, Utilizes Cathepsin L to Infect ACE2-expressing Cells. J. Biol. Chem. 2006, 281, 3198–3203. [Google Scholar] [CrossRef]
  74. Pišlar, A.; Mitrović, A.; Sabotič, J.; Fonović, U.P.; Nanut, M.P.; Jakoš, T.; Senjor, E.; Kos, J. The role of cysteine peptidases in coronavirus cell entry and replication: The therapeutic potential of cathepsin inhibitors. PLoS Pathog. 2020, 16, e1009013. [Google Scholar] [CrossRef]
  75. Millet, J.K.; Whittaker, G.R. Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015, 202, 120–134. [Google Scholar] [CrossRef]
  76. Li, F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol. 2016, 3, 237–261. [Google Scholar] [CrossRef]
  77. Hartenian, E.; Nandakumar, D.; Lari, A.; Ly, M.; Tucker, J.M.; Glaunsinger, B.A. The molecular virology of coronaviruses. J. Biol. Chem. 2020, 295, 12910–12934. [Google Scholar] [CrossRef]
  78. Park, J.-E.; Li, K.; Barlan, A.; Fehr, A.R.; Perlman, S.; McCray, P.B.; Gallagher, T. Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism. Proc. Natl. Acad. Sci. USA 2016, 113, 12262–12267. [Google Scholar] [CrossRef]
  79. Kleine-Weber, H.; Elzayat, M.T.; Hoffmann, M.; Pöhlmann, S. Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein. Sci. Rep. 2018, 8, 16597. [Google Scholar] [CrossRef]
  80. Shang, J.; Wan, Y.; Luo, C.; Ye, G.; Geng, Q.; Auerbach, A.; Li, F. Cell entry mechanisms of SARS-CoV-2. Proc. Natl. Acad. Sci. USA 2020, 117, 11727–11734. [Google Scholar] [CrossRef]
  81. Jaimes., J.; Millet, J.; Whittaker, G. Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1/S2 Site. SSRN 2020, 3581359, preprintUpdate in iScience 2020, 23, 101212. [Google Scholar] [CrossRef]
  82. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280.e8. [Google Scholar] [CrossRef]
  83. Seyran, M.; Takayama, K.; Uversky, V.N.; Lundstrom, K.; Palù, G.; Sherchan, S.P.; Attrish, D.; Rezaei, N.; Aljabali, A.A.A.; Ghosh, S.; et al. The structural basis of accelerated host cell entry by SARS-CoV-2. FEBS J. 2021, 288, 5010–5020. [Google Scholar] [CrossRef]
  84. Zhao, M.-M.; Yang, W.-L.; Yang, F.-Y.; Zhang, L.; Huang, W.-J.; Hou, W.; Fan, C.-F.; Jin, R.-H.; Feng, Y.-M.; Wang, Y.-C.; et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal Transduct. Target. Ther. 2021, 6, 134. [Google Scholar] [CrossRef]
  85. Bollavaram, K.; Leeman, T.H.; Lee, M.W.; Kulkarni, A.; Upshaw, S.G.; Yang, J.; Song, H.; Platt, M.O. Multiple sites on SARS-CoV-2 spike protein are susceptible to proteolysis by cathepsins B, K, L, S, and V. Protein Sci. 2021, 30, 1131–1143. [Google Scholar] [CrossRef]
  86. Edinger, T.O.; Pohl, M.; Yángüez, E.; Stertz, S. Cathepsin W Is Required for Escape of Influenza A Virus from Late Endosomes. mBio 2015, 6, e00297-15. [Google Scholar] [CrossRef]
  87. Pager, C.T.; Dutch, R.E. Cathepsin L Is Involved in Proteolytic Processing of the Hendra Virus Fusion Protein. J. Virol. 2005, 79, 12714–12720. [Google Scholar] [CrossRef]
  88. Diederich, S.; Sauerhering, L.; Weis, M.; Altmeppen, H.; Schaschke, N.; Reinheckel, T.; Erbar, S.; Maisner, A. Activation of the Nipah Virus Fusion Protein in MDCK Cells Is Mediated by Cathepsin B within the Endosome-Recycling Compartment. J. Virol. 2012, 86, 3736–3745. [Google Scholar] [CrossRef]
  89. Hadigal, S.; Koganti, R.; Yadavalli, T.; Agelidis, A.; Suryawanshi, R.; Shukla, D. Heparanase-Regulated Syndecan-1 Shedding Facilitates Herpes Simplex Virus 1 Egress. J. Virol. 2020, 94, e01672–e01719. [Google Scholar] [CrossRef] [PubMed]
  90. Agelidis, A.; Shukla, D. Heparanase, Heparan Sulfate and Viral Infection. Adv. Exp. Med. Biol. 2019, 1221, 759–770. [Google Scholar] [CrossRef]
  91. Vlodavsky, I.; Ilan, N.; Sanderson, R.D. Forty Years of Basic and Translational Heparanase Research. Adv. Exp. Med. Biol. 2020, 1221, 3–59. [Google Scholar] [CrossRef] [PubMed]
  92. Vlodavsky, I.; Barash, U.; Nguyen, H.M.; Yang, S.-M.; Ilan, N. Biology of the Heparanase-Heparan Sulfate Axis and Its Role in Disease Pathogenesis. Semin. Thromb. Hemost. 2021, 47, 240–253. [Google Scholar] [CrossRef]
  93. Mayfosh, A.J.; Nguyen, T.K.; Hulett, M.D. The Heparanase Regulatory Network in Health and Disease. Int. J. Mol. Sci. 2021, 22, 11096. [Google Scholar] [CrossRef]
  94. De Pasquale, V.; Quiccione, M.; Tafuri, S.; Avallone, L.; Pavone, L. Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2. Int. J. Mol. Sci. 2021, 22, 6574. [Google Scholar] [CrossRef]
  95. Abboud-Jarrous, G.; Atzmon, R.; Peretz, T.; Palermo, C.; Gadea, B.B.; Joyce, J.A.; Vlodavsky, I. Cathepsin L Is Responsible for Processing and Activation of Proheparanase through Multiple Cleavages of a Linker Segment. J. Biol. Chem. 2008, 283, 18167–18176. [Google Scholar] [CrossRef]
  96. Iozzo, R.V.; Schaefer, L. Proteoglycan form and function: A comprehensive nomenclature of proteoglycans. Matrix Biol. 2015, 42, 11–55. [Google Scholar] [CrossRef]
  97. Khanna, M.; Parish, C.R. Heparanase: Historical Aspects and Future Perspectives. Adv. Exp. Med. Biol. 2020, 1221, 71–96. [Google Scholar] [CrossRef]
  98. Billings, P.C.; Pacifici, M. Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: Mechanisms and mysteries. Connect. Tissue Res. 2015, 56, 272–280. [Google Scholar] [CrossRef]
  99. Cagno, V.; Tseligka, E.D.; Jones, S.T.; Tapparel, C. Heparan sulfate proteoglycans and viral attachment: True receptors or adaptation bias? Viruses 2019, 11, 596. [Google Scholar] [CrossRef]
  100. Clausen, T.M.; Sandoval, D.R.; Spliid, C.B.; Pihl, J.; Perrett, H.R.; Painter, C.D.; Narayanan, A.; Majowicz, S.A.; Kwong, E.M.; McVicar, R.N.; et al. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell 2020, 183, 1043–1057.e15. [Google Scholar] [CrossRef]
  101. Zhang, Q.; Chen, C.Z.; Swaroop, M.; Xu, M.; Wang, L.; Lee, J.; Wang, A.Q.; Pradhan, M.; Hagen, N.; Chen, L.; et al. Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro. Cell Discov. 2020, 6, 80. [Google Scholar] [CrossRef]
  102. Hadigal, S.R.; Agelidis, A.M.; Karasneh, G.A.; Antoine, T.E.; Yakoub, A.M.; Ramani, V.C.; Djalilian, A.R.; Sanderson, R.D.; Shukla, D. Heparanase is a host enzyme required for herpes simplex virus-1 release from cells. Nat. Commun. 2015, 6, 6985. [Google Scholar] [CrossRef]
  103. Hopkins, J.; Yadavalli, T.; Agelidis, A.M.; Shukla, D. Host Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus 2 Release from Cells. J. Virol. 2018, 92, e01179-18. [Google Scholar] [CrossRef]
  104. Guo, C.; Zhu, Z.; Guo, Y.; Wang, X.; Yu, P.; Xiao, S.; Chen, Y.; Cao, Y.; Liu, X. Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release. J. Virol. 2017, 91, e00625-17. [Google Scholar] [CrossRef]
  105. Puerta-Guardo, H.; Glasner, D.; Harris, E. Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability. PLoS Pathog. 2016, 12, e1005738. [Google Scholar] [CrossRef]
  106. Thakkar, N.; Yadavalli, T.; Jaishankar, D.; Shukla, D. Emerging Roles of Heparanase in Viral Pathogenesis. Pathogens 2017, 6, 43. [Google Scholar] [CrossRef]
  107. Surviladze, Z.; Sterkand, R.T.; Ozbun, M.A. Interaction of human papillomavirus type 16 particles with heparan sulfate and syndecan-1 molecules in the keratinocyte extracellular matrix plays an active role in infection. J. Gen. Virol. 2015, 96, 2232–2241. [Google Scholar] [CrossRef]
  108. Tao, Y.; Wang, Z.; Zhou, Y. Expression of heparanase in kidney of rats with respiratory syncytial virus nephropathy and its relationship with proteinurina. Sichuan Da Xue Xue Bao Yi Xue Ban 2014, 45, 212–215. (In Chinese) [Google Scholar]
  109. Barth, H.; Schnober, E.K.; Zhang, F.; Linhardt, R.J.; Depla, E.; Boson, B.; Cosset, F.-L.; Patel, A.H.; Blum, H.E.; Baumert, T.F. Viral and Cellular Determinants of the Hepatitis C Virus Envelope-Heparan SulfateInteraction. J. Virol. 2006, 80, 10579–10590. [Google Scholar] [CrossRef]
  110. Buijsers, B.; Yanginlar, C.; de Nooijer, A.; Grondman, I.; Maciej-Hulme, M.L.; Jonkman, I.; Janssen, N.A.F.; Rother, N.; de Graaf, M.; Pickkers, P.; et al. Increased Plasma Heparanase Activity in COVID-19 Patients. Front. Immunol. 2020, 11, 575047. [Google Scholar] [CrossRef]
  111. Koganti, R.; Suryawanshi, R.; Shukla, D. Heparanase, cell signaling, and viral infections. Cell Mol. Life Sci. 2020, 77, 5059–5077. [Google Scholar] [CrossRef] [PubMed]
  112. Kinaneh, S.; Khamaysi, I.; Karram, T.; Hamoud, S. Heparanase as a potential player in SARS-CoV-2 infection and induced coagulopathy. Biosci. Rep. 2021, 41, BSR20210290. [Google Scholar] [CrossRef] [PubMed]
  113. Rudensky, A.; Beers, C. Lysosomal Cysteine Proteases and Antigen Presentation. Ernst. Scher. Res. Found Workshop 2006, 56, 81–95. [Google Scholar] [CrossRef]
  114. Kopitar-Jerala, N. The Role of Cysteine Proteinases and their Inhibitors in the Host-Pathogen Cross Talk. Curr. Protein Pept. Sci. 2012, 13, 767–775. [Google Scholar] [CrossRef] [PubMed]
  115. Manoury, B. Proteases: Essential Actors in Processing Antigens and Intracellular Toll-Like Receptors. Front. Immunol. 2013, 4, 299. [Google Scholar] [CrossRef]
  116. Jakoš, T.; Pišlar, A.; Jewett, A.; Kos, J. Cysteine Cathepsins in Tumor-Associated Immune Cells. Front. Immunol. 2019, 10, 2037. [Google Scholar] [CrossRef]
  117. Mielcarska, M.B.; Bossowska-Nowicka, M.; Toka, F.N. Cell Surface Expression of Endosomal Toll-Like Receptors—A Necessity or a Superfluous Duplication? Front. Immunol. 2021, 11, 620972. [Google Scholar] [CrossRef]
  118. Foronjy, R.F.; Taggart, C.; Dabo, A.J.; Weldon, S.; Cummins, N.; Geraghty, P. Type-I interferons induce lung protease responses following respiratory syncytial virus infection via RIG-I-like receptors. Mucosal Immunol. 2015, 8, 161–175. [Google Scholar] [CrossRef]
  119. Embgenbroich, M.; Burgdorf, S. Current Concepts of Antigen Cross-Presentation. Front. Immunol. 2018, 9, 1643. [Google Scholar] [CrossRef]
  120. Strumillo, S.T.; Kartavykh, D.; de Carvalho, F.F., Jr.; Cruz, N.C.; de Souza Teodoro, A.C.; Sobhie Diaz, R.; Curcio, M.F. Host-virus interaction and viral evasion. Cell Biol. Int. 2021, 45, 1124–1147. [Google Scholar] [CrossRef]
  121. Bossowska-Nowicka, M.; Mielcarska, M.B.; Romaniewicz, M.; Kaczmarek, M.M.; Gregorczyk-Zboroch, K.P.; Struzik, J.; Grodzik, M.; Gieryńska, M.M.; Toka, F.N.; Szulc-Dąbrowska, L. Ectromelia virus suppresses expression of cathepsins and cystatins in conventional dendritic cells to efficiently execute the replication process. BMC Microbiol. 2019, 19, 92. [Google Scholar] [CrossRef]
  122. Harman, A.N.; Kraus, M.; Bye, C.R.; Byth, K.; Turville, S.G.; Tang, O.; Mercier, S.K.; Nasr, N.; Stern, J.L.; Slobedman, B.; et al. HIV-1-infected dendritic cells show 2 phases of gene expression changes, with lysosomal enzyme activity decreased during the second phase. Blood 2009, 114, 85–94. [Google Scholar] [CrossRef]
  123. Burster, T.; Giffon, T.; Dahl, M.E.; Björck, P.; Bogyo, M.; Weber, E.; Mahmood, K.; Lewis, D.B.; Mellins, E.D. Influenza A virus elevates active cathepsin B in primary murine DC. Int. Immunol. 2007, 19, 645–655. [Google Scholar] [CrossRef]
  124. Coleman, M.D.; Ha, S.D.; Haeryfar, S.M.; Barr, S.D.; Kim, S.O. Cathepsin B Plays a Key Role in Optimal Production of the Influenza A- Virus. J. Virol. Antivir. Res. 2018, 7, 1–20. [Google Scholar] [CrossRef]
  125. Kim, H.; Mazumdar, B.; Bose, S.K.; Meyer, K.; Di Bisceglie, A.M.; Hoft, D.F.; Ray, R. Hepatitis C Virus-Mediated Inhibition of Cathepsin S Increases Invariant-Chain Expression on Hepatocyte Surface. J. Virol. 2012, 86, 9919–9928. [Google Scholar] [CrossRef]
  126. Hu, W.; Yen, Y.-T.; Singh, S.; Kao, C.-L.; Wu-Hsieh, B.A. SARS-CoV Regulates Immune Function-Related Gene Expression in Human Monocytic Cells. Viral Immunol. 2012, 25, 277–288. [Google Scholar] [CrossRef]
  127. Crow, M.S.; Lum, K.K.; Sheng, X.; Song, B.; Cristea, I.M. Diverse mechanisms evolved by DNA viruses to inhibit early host defenses. Crit. Rev. Biochem. Mol. Biol. 2016, 51, 452–481. [Google Scholar] [CrossRef]
  128. Li, D.; Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 2021, 6, 291. [Google Scholar] [CrossRef]
  129. Rex, D.A.B.; Prasad, T.S.K.; Kandasamy, R.K. Revisiting Regulated Cell Death Responses in Viral Infections. Int. J. Mol. Sci. 2022, 23, 7023. [Google Scholar] [CrossRef]
  130. Fay, E.J.; Aron, S.L.; Macchietto, M.G.; Markman, M.W.; Esser-Nobis, K.; Gale, M.; Shen, S.; Langlois, R.A. Cell type- and replication stage-specific influenza virus responses in vivo. PLoS Pathog. 2020, 16, e1008760. [Google Scholar] [CrossRef]
  131. Malik, G.; Zhou, Y. Innate Immune Sensing of Influenza A Virus. Viruses 2020, 12, 755. [Google Scholar] [CrossRef]
  132. Lamotte, L.-A.; Tafforeau, L. How Influenza A Virus NS1 Deals with the Ubiquitin System to Evade Innate Immunity. Viruses 2021, 13, 2309. [Google Scholar] [CrossRef]
  133. Ma, J.; Sun, Q.; Mi, R.; Zhang, H. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling. J. Genet. Genom. 2011, 38, 533–537. [Google Scholar] [CrossRef]
  134. Gannagé, M.; Dormann, D.; Albrecht, R.; Dengjel, J.; Torossi, T.; Rämer, P.C.; Lee, M.; Strowig, T.; Arrey, F.; Conenello, G.; et al. Matrix Protein 2 of Influenza A Virus Blocks Autophagosome Fusion with Lysosomes. Cell Host Microbe 2009, 6, 367–380. [Google Scholar] [CrossRef]
  135. Beale, R.; Wise, H.; Stuart, A.; Ravenhill, B.J.; Digard, P.; Randow, F. A LC3-Interacting Motif in the Influenza A Virus M2 Protein Is Required to Subvert Autophagy and Maintain Virion Stability. Cell Host Microbe 2014, 15, 239–247. [Google Scholar] [CrossRef]
  136. Galluzzi, L.; Brenner, C.; Morselli, E.; Touat, Z.; Kroemer, G. Viral Control of Mitochondrial Apoptosis. PLoS Pathog. 2008, 4, e1000018. [Google Scholar] [CrossRef]
  137. Liu, B.; Fang, M.; Hu, Y.; Huang, B.; Li, N.; Chang, C.; Huang, R.; Xu, X.; Yang, Z.; Chen, Z.; et al. Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation. Autophagy 2014, 10, 416–430. [Google Scholar] [CrossRef]
  138. Furman, L.M.; Maaty, W.S.; Petersen, L.K.; Ettayebi, K.; Hardy, M.E.; Bothner, B. Cysteine protease activation and apoptosis in Murine norovirus infection. Virol. J. 2009, 6, 139. [Google Scholar] [CrossRef]
  139. Morchang, A.; Panaampon, J.; Suttitheptumrong, A.; Yasamut, U.; Noisakran, S.; Yenchitsomanus, P.-T.; Limjindaporn, T. Role of cathepsin B in dengue virus-mediated apoptosis. Biochem. Biophys. Res. Commun. 2013, 438, 20–25. [Google Scholar] [CrossRef]
  140. Wang, Y.; Jia, L.; Shen, J.; Wang, Y.; Fu, Z.; Su, S.-A.; Cai, Z.; Wang, J.-A.; Xiang, M. Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis. PLoS Pathog. 2018, 14, e1006872. [Google Scholar] [CrossRef]
  141. Fung, S.-Y.; Yuen, K.-S.; Ye, Z.-W.; Chan, C.-P.; Jin, D.-Y. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: Lessons from other pathogenic viruses. Emerg. Microbes Infect. 2020, 9, 558–570. [Google Scholar] [CrossRef]
  142. Xiong, Y.; Liu, Y.; Cao, L.; Wang, D.; Guo, M.; Jiang, A.; Guo, D.; Hu, W.; Yang, J.; Tang, Z.; et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg. Microbes Infect. 2020, 9, 761–770. [Google Scholar] [CrossRef] [PubMed]
  143. Andoniou, C.E.; Fleming, P.; Sutton, V.R.; Trapani, J.A.; Degli-Esposti, M.A. Cathepsin C limits acute viral infection independently of NK cell and CD8+ T-cell cytolytic function. Immunol. Cell Biol. 2010, 89, 540–548. [Google Scholar] [CrossRef] [PubMed]
  144. Rawlings, N.D.; Barrett, A.J.; Thomas, P.D.; Huang, X.; Bateman, A.; Finn, R.D. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res. 2018, 46, D624–D632. [Google Scholar] [CrossRef] [PubMed]
  145. Liu, T.; Luo, S.; Libby, P.; Shi, G.-P. Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients. Pharmacol. Ther. 2020, 213, 107587. [Google Scholar] [CrossRef]
  146. Zhou, Y.; Vedantham, P.; Lu, K.; Agudelo, J.; Carrion, R., Jr.; Nunneley, J.W.; Barnard, D.; Pöhlmann, S.; McKerrow, J.H.; Renslo, A.R.; et al. Protease inhibitors targeting coronavirus and filovirus entry. Antivir. Res. 2015, 116, 76–84. [Google Scholar] [CrossRef]
  147. Baranov, M.; Bianchi, F.; Schirmacher, A.; van Aart, M.A.; Maassen, S.; Muntjewerff, E.M.; Dingjan, I.; ter Beest, M.; Verdoes, M.; Keyser, S.G.; et al. The Phosphoinositide Kinase PIKfyve Promotes Cathepsin-S-Mediated Major Histocompatibility Complex Class II Antigen Presentation. iScience 2018, 11, 160–177. [Google Scholar] [CrossRef]
  148. Riva, L.; Yuan, S.; Yin, X.; Martin-Sancho, L.; Matsunaga, N.; Pache, L.; Burgstaller-Muehlbacher, S.; De Jesus, P.D.; Teriete, P.; Hull, M.V.; et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nat. Cell Biol. 2020, 586, 113–119. [Google Scholar] [CrossRef]
  149. Kreutzberger, A.J.B.; Sanyal, A.; Ojha, R.; Pyle, J.D.; Vapalahti, O.; Balistreri, G.; Kirchhausen, T. Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease. J. Virol. 2021, 95, e0097521. [Google Scholar] [CrossRef]
  150. Baranov, M.V.; Bianchi, F.; van den Bogaart, G. The PIKfyve Inhibitor Apilimod: A Double-Edged Sword against COVID-19. Cells 2020, 10, 30. [Google Scholar] [CrossRef]
  151. Gnirß, K.; Kühl, A.; Karsten, C.; Glowacka, I.; Bertram, S.; Kaup, F.; Hofmann, H.; Pöhlmann, S. Cathepsins B and L activate Ebola but not Marburg virus glycoproteins for efficient entry into cell lines and macrophages independent of TMPRSS2 expression. Virology 2012, 424, 3–10. [Google Scholar] [CrossRef]
  152. Tharappel, A.M.; Samrat, S.K.; Li, Z.; Li, H. Targeting Crucial Host Factors of SARS-CoV-2. ACS Infect. Dis. 2020, 6, 2844–2865. [Google Scholar] [CrossRef]
  153. Björck, L.; Grubb, A.; Kjellén, L. Cystatin C, a human proteinase inhibitor, blocks replication of herpes simplex virus. J. Virol. 1990, 64, 941–943. [Google Scholar] [CrossRef]
  154. Xiang, R.; Yu, Z.; Wang, Y.; Wang, L.; Huo, S.; Li, Y.; Liang, R.; Hao, Q.; Ying, T.; Gao, Y.; et al. Recent advances in developing small-molecule inhibitors against SARS-CoV-2. Acta Pharm. Sin. B 2022, 12, 1591–1623. [Google Scholar] [CrossRef]
  155. Estoppey, D.; Lee, C.M.; Janoschke, M.; Lee, B.H.; Wan, K.F.; Dong, H.; Mathys, P.; Filipuzzi, I.; Schuhmann, T.; Riedl, R.; et al. The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase. Cell Rep. 2017, 19, 451–460. [Google Scholar] [CrossRef]
  156. Zhang, X.; Liu, Q.; Zhang, N.; Li, Q.; Liu, Z.; Li, Y.; Gao, L.; Wang, Y.; Deng, H.; Song, D. Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage. Eur. J. Med. Chem. 2018, 149, 45–55. [Google Scholar] [CrossRef]
  157. Dana, D.; Pathak, S.K. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 2020, 25, 698. [Google Scholar] [CrossRef]
  158. Mayer, A.; Guerrero, A.; Rodríguez, A.; Taglialatela-Scafati, O.; Nakamura, F.; Fusetani, N. Marine Pharmacology in 2016–2017: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action. Mar. Drugs 2021, 19, 49. [Google Scholar] [CrossRef]
  159. Christy, M.P.; Uekusa, Y.; Gerwick, L.; Gerwick, W.H. Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2. J. Nat. Prod. 2020, 84, 161–182. [Google Scholar] [CrossRef]
  160. Vidal-Albalat, A.; González, F.V. Natural Products as Cathepsin Inhibitors. Stud. Nat. Prod. Chem. 2016, 50, 179–213. [Google Scholar] [CrossRef]
  161. Ebert, D.H.; Wetzel, J.D.; Brumbaugh, D.E.; Chance, S.R.; Stobie, L.E.; Baer, G.S.; Dermody, T.S. Adaptation of Reovirus to Growth in the Presence of Protease Inhibitor E64 Segregates with a Mutation in the Carboxy Terminus of Viral Outer-Capsid Protein sigma3. J. Virol. 2001, 75, 3197–3206. [Google Scholar] [CrossRef]
  162. Pillaiyar, T.; Meenakshisundaram, S.; Manickam, M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov. Today 2020, 25, 668–688. [Google Scholar] [CrossRef]
  163. Miller, B.; Friedman, A.J.; Choi, H.; Hogan, J.; McCammon, J.A.; Hook, V.; Gerwick, W.H. The Marine Cyanobacterial Metabolite Gallinamide a Is a Potent and Selective Inhibitor of Human Cathepsin L. J. Nat. Prod. 2013, 77, 92–99. [Google Scholar] [CrossRef]
  164. Fusetani, N.; Fujita, M.; Nakao, Y.; Matsunaga, S.; van Soest, R.W. Tokaramide A, a new cathepsin B inhibitor from the marine sponge Theonella aff. mirabilis. Bioorg. Med. Chem. Lett. 1999, 9, 3397–3402. [Google Scholar] [CrossRef]
  165. Nakao, Y.; Fujita, M.; Warabi, K.; Matsunaga, A.S.; Fusetani, N. Miraziridine A, a Novel Cysteine Protease Inhibitor from the Marine Sponge Theonella aff. mirabilis. J. Am. Chem. Soc. 2000, 122, 10462–10463. [Google Scholar] [CrossRef]
  166. Ashhurst, A.S.; Tang, A.H.; Fajtová, P.; Yoon, M.C.; Aggarwal, A.; Bedding, M.J.; Stoye, A.; Beretta, L.; Pwee, D.; Drelich, A.; et al. Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L. J. Med. Chem. 2022, 65, 2956–2970. [Google Scholar] [CrossRef]
  167. Dang, Z.; Zhu, L.; Lai, W.; Bogerd, H.; Lee, K.-H.; Huang, L.; Chen, C.-H. Aloperine and Its Derivatives as a New Class of HIV-1 Entry Inhibitors. ACS Med. Chem. Lett. 2016, 7, 240–244. [Google Scholar] [CrossRef]
  168. Lv, X.-Q.; Zou, L.-L.; Tan, J.-L.; Li, H.; Li, J.-R.; Liu, N.-N.; Dong, B.; Song, D.-Q.; Peng, Z.-G. Aloperine inhibits hepatitis C virus entry into cells by disturbing internalisation from endocytosis to the membrane fusion process. Eur. J. Pharmacol. 2020, 883, 173323. [Google Scholar] [CrossRef]
  169. Dang, Z.; Jung, K.; Zhu, L.; Lai, W.; Xie, H.; Lee, K.-H.; Huang, L.; Chen, C.-H. Identification and Synthesis of Quinolizidines with Anti-Influenza A Virus Activity. ACS Med. Chem. Lett. 2014, 5, 942–946. [Google Scholar] [CrossRef]
  170. Agbowuro, A.A.; Huston, W.M.; Gamble, A.B.; Tyndall, J.D.A. Proteases and protease inhibitors in infectious diseases. Med. Res. Rev. 2018, 38, 1295–1331. [Google Scholar] [CrossRef]
Ijms 23 09089 g001 550
Figure 1. Physiological and pathological roles of cathepsins depending on their localization at a specific cellular compartment.
Figure 1. Physiological and pathological roles of cathepsins depending on their localization at a specific cellular compartment.
Ijms 23 09089 g001
Table
Table 1. Cathepsins Involved in Human Viral Infections and Their Mechanism of Action.
Table 1. Cathepsins Involved in Human Viral Infections and Their Mechanism of Action.
CathepsinMW *
(kDa)		Cellular LocalizationEnzymatic ActivityInteracting VirusMechanism of Action
Serine cathepsins
A54Endo/lysosomeEndopeptidase, CarboxypeptidaseSARS-CoVAntigen processing downregulation [126]
G29Endo/lysosome
Extracellular space		EndopeptidaseRespiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
Aspartate cathepsins
D45Endo/lysosome
Cytosol
Extracellular space		EndopeptidaseHepatitis BAutophagy impairment [137]
E43Endo/lysosomeEndopeptidaseRespiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
Cysteine cathepsins
B38Endo/lysosome
Cytosol
Nucleus
Plasma membrane
Extracellular space		Endopeptidase, CarboxypeptidaseEbolaProcessing of viral glycoprotein prior to fusion with the cell membrane [63,64,65]
Human papilloma virus type 16Binding, internalization and trafficking at the plasma membrane, in the endolysosome, or vesicles [67,69]
ReovirusesDisassembly of the viral particles in the late endosomes [70,71,72]
SARS-CoV and SARS-CoV-2Activation of S protein for entry by endocytosis [74,75,80,81,85]
NipahProcessing viral fusion protein [88]
EctromeliaImmune response impairment and replication induction [121]
Human immunodeficiency virus type 1Decreased antigen processing and presentation, replication [122]
Influenza AImpaired MHC II antigen processing [123]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
NorovirusesActivation of apoptosis and replication induction [138]
DengueApoptosis activation [139]
>Coxsackievirus B3Inflammasome activation, pyroptosis [140]
C52Endo/lysosome
Cytosol		EndopeptidaseHuman immunodeficiency virus type 1Decreased antigen processing and presentation, replication [122]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
CytomegalovirusInhibition of viral replication [143]
H37Endo/lysosome
Nucleus		Endopeptidase,
Aminopeptidase		SARS-CoVAntigen processing downregulation [126]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
K37Endo/lysosome
Nucleus
Extracellular space		EndopeptidaseSARS-CoV-2Protein S processing [85]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
L38Endo/lysosome
Cytosol
Nucleus
Plasma membrane
Secretory vesicles
Extracellular space		EndopeptidaseEbolaProcessing of viral glycoprotein prior to fusion with the cell membrane [63,64,65,66]
Human papilloma virus type 16Binding, internalization and trafficking at the plasma membrane, in the endolysosome, or vesicles [67,69]
ReovirusesDisassembly of the viral particles in the late endosomes [70,71,72]
SARS-CoV, MERS-CoV and SARS-CoV-2Activation of S protein for entry by either fusion or endocytosis [73,74,75,78,79,80,81,82,83,84,85]; apoptosis activation facilitating viral dissemination [141,142]
HendraProcessing of the viral fusion protein [87]
Herpes Simplex Virus -1 and -2Heparanase up-regulation, viral egress [89,95,102,103]
DengueHeparanase up-regulation, viral egress [105,106]
EctromeliaImmune response escape, replication [121]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
S37Endo/lysosome
Cytosol
Nucleus
Plasma membrane
Extracellular space		EndopeptidaseReovirusesDisassembly of the viral particles in the late endosomes [71]
SARS-CoV-2Protein S processing [85]
EctromeliaImmune response escape, replication [121]
Human immunodeficiency virus type 1Decreased antigen processing and presentation, replication [122]
Hepatitis CImpairment of MHC II maturation [125]
SARS-CoVAntigen processing downregulation [126]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
DengueActivation of apoptosis [139]
V37Endo/lysosome
Secretory vesicles
Extracellular space		EndopeptidaseSARS-CoV-2Protein S processing [85]
W42Endo/lysosome
Extracellular space		EndopeptidaseInfluenza AEscape from late endosomes [86]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
Z34Endo/lysosome
Cytosol		EndopeptidaseHuman immunodeficiency virus type 1Decreased antigen processing and presentation, replication [122]
Respiratory syncytial virusActivation of pattern recognition receptors and immune response hijacking [118]
* Molecular weight.
Table
Table 2. Examples of effective cathepsin inhibitors for the treatment of infection diseases caused by viruses.
Table 2. Examples of effective cathepsin inhibitors for the treatment of infection diseases caused by viruses.
TargetInhibitorVirus(es)Reference(s)
Cysteine cathepsinsK11777EBOV, Paramyxoviruses, CoVs[146]
ApilimodSARS-CoV-2[147,148,149]
Cathepsins B and/or LMDL 28170EBOV, SARS-CoV-1, SARS-CoV-2[148,151,152]
Z LVG CHN2HSV
MERS and SARS-CoV-2		[153]
[148,154]
Gallinamide ASARS-CoV-2[166]
AloperineEBOV
HIV-1
HCV
IAV		[156]
[167]
[168]
[169]
E-64Reoviruses
RSV
MERS and SARS-CoV-2		[161]
[118]
[162]
Cathepsin KONO 5334SARS-CoV-2[148]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Scarcella, M.; d’Angelo, D.; Ciampa, M.; Tafuri, S.; Avallone, L.; Pavone, L.M.; De Pasquale, V. The Key Role of Lysosomal Protease Cathepsins in Viral Infections. Int. J. Mol. Sci. 2022, 23, 9089. https://doi.org/10.3390/ijms23169089

AMA Style

Scarcella M, d’Angelo D, Ciampa M, Tafuri S, Avallone L, Pavone LM, De Pasquale V. The Key Role of Lysosomal Protease Cathepsins in Viral Infections. International Journal of Molecular Sciences. 2022; 23(16):9089. https://doi.org/10.3390/ijms23169089

Chicago/Turabian Style

Scarcella, Melania, Danila d’Angelo, Mariangela Ciampa, Simona Tafuri, Luigi Avallone, Luigi Michele Pavone, and Valeria De Pasquale. 2022. "The Key Role of Lysosomal Protease Cathepsins in Viral Infections" International Journal of Molecular Sciences 23, no. 16: 9089. https://doi.org/10.3390/ijms23169089

APA Style

Scarcella, M., d’Angelo, D., Ciampa, M., Tafuri, S., Avallone, L., Pavone, L. M., & De Pasquale, V. (2022). The Key Role of Lysosomal Protease Cathepsins in Viral Infections. International Journal of Molecular Sciences, 23(16), 9089. https://doi.org/10.3390/ijms23169089

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop