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The Role of Protease Inhibitors in Infectious Diseases
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The Role of Protease Inhibitors in Infectious Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 9955

Special Issue Editor

Dr. Jun Wang

E-Mail Website
Guest Editor
Departments of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA
Interests: structure-based drug design, high-throughput screening, medicinal chemistry, electrophysiology, peptide chemistry, biophysics, virology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Proteases from numerous pathogenic organisms have been actively pursued as drug targets. In addition to the clinical success of HIV and HCV protease inhibitors, the recent approval of the COVID-19 oral drug Paxlovid represents a major advance in our efforts in targeting the viral proteases. In addition to their critical roles in viral infections, proteases are also vital in the replication of many other pathogens including bacteria, fungi, malaria, and prions. Although numerous protease inhibitors have been reported, the majority of them failed to advance to animal models and clinical trials due to the limitations of low target selectivity, poor stability, a lack of oral bioavailability, and unfavorable pharmacokinetic properties associated with the peptide scaffold. As such, this Special Issue is organized to solicit submissions that will address these key issues. Both review articles and research articles addressing the current advances and state-of-art research of protease in the infectious disease field are welcomed.

Potential topics include but are not limited to the following:

  • Drug-target validation of protease in infectious diseases
  • Protease inhibitor design and optimization
  • Covalent, non-covalent, and cyclized protease inhibitors
  • Optimization of the pharmacokinetic properties of protease inhibitors
  • Resistance study of protease inhibitors
  • Structural biology of protease in complex with inhibitors
  • Drug formulation and delivery of protease inhibitors to treat infectious diseases
  • Combination therapy with protease inhibitors
  • Computational modeling
  • Assay development for proteases

Dr. Jun Wang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • infectious diseases
  • proteases
  • drug discovery
  • assay development
  • antivirals
  • antifungals
  • antibiotics
  • X-ray

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Published Papers (4 papers)

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Research

15 pages, 2201 KiB  
Article
Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease
by Qian Wang, Guofeng Chen, Jian He, Jiameng Li, Muya Xiong, Haixia Su, Minjun Li, Hangchen Hu and Yechun Xu
Int. J. Mol. Sci. 2023, 24(10), 8633; https://doi.org/10.3390/ijms24108633 - 11 May 2023
Cited by 4 | Viewed by 2651
Abstract
The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide [...] Read more.
The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PLpro. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC50 = 0.23 μM) and significant inhibition of SARS-CoV-2 PLpro in the HEK293T cells using a cell-based protease assay (EC50 = 3.61 μM). Moreover, an X-ray crystal structure of SARS-CoV-2 PLpro in complex with compound 2 confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PLpro inhibitors and provide an attractive starting point for further optimization. Full article
(This article belongs to the Special Issue The Role of Protease Inhibitors in Infectious Diseases)
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18 pages, 3197 KiB  
Article
Targeting the I7L Protease: A Rational Design for Anti-Monkeypox Drugs?
by Andrea Dodaro, Matteo Pavan and Stefano Moro
Int. J. Mol. Sci. 2023, 24(8), 7119; https://doi.org/10.3390/ijms24087119 - 12 Apr 2023
Cited by 6 | Viewed by 2743
Abstract
The latest monkeypox virus outbreak in 2022 showcased the potential threat of this viral zoonosis to public health. The lack of specific treatments against this infection and the success of viral protease inhibitors-based treatments against HIV, Hepatitis C, and SARS-CoV-2, brought the monkeypox [...] Read more.
The latest monkeypox virus outbreak in 2022 showcased the potential threat of this viral zoonosis to public health. The lack of specific treatments against this infection and the success of viral protease inhibitors-based treatments against HIV, Hepatitis C, and SARS-CoV-2, brought the monkeypox virus I7L protease under the spotlight as a potential target for the development of specific and compelling drugs against this emerging disease. In the present work, the structure of the monkeypox virus I7L protease was modeled and thoroughly characterized through a dedicated computational study. Furthermore, structural information gathered in the first part of the study was exploited to virtually screen the DrugBank database, consisting of drugs approved by the Food and Drug Administration (FDA) and clinical-stage drug candidates, in search for readily repurposable compounds with similar binding features as TTP-6171, the only non-covalent I7L protease inhibitor reported in the literature. The virtual screening resulted in the identification of 14 potential inhibitors of the monkeypox I7L protease. Finally, based on data collected within the present work, some considerations on developing allosteric modulators of the I7L protease are reported. Full article
(This article belongs to the Special Issue The Role of Protease Inhibitors in Infectious Diseases)
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13 pages, 3439 KiB  
Article
Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CLpro
by Ling Ma, Yongli Xie, Mei Zhu, Dongrong Yi, Jianyuan Zhao, Saisai Guo, Yongxin Zhang, Jing Wang, Quanjie Li, Yucheng Wang and Shan Cen
Int. J. Mol. Sci. 2022, 23(24), 16011; https://doi.org/10.3390/ijms232416011 - 16 Dec 2022
Cited by 3 | Viewed by 1950
Abstract
The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for [...] Read more.
The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CLpro through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CLpro potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CLpro in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CLpro through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CLpro warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19. Full article
(This article belongs to the Special Issue The Role of Protease Inhibitors in Infectious Diseases)
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15 pages, 4024 KiB  
Article
Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants
by Ling Ma, Jiajia Wen, Biao Dong, Jinming Zhou, Shangjiu Hu, Juxian Wang, Yucheng Wang, Mei Zhu and Shan Cen
Int. J. Mol. Sci. 2022, 23(22), 14178; https://doi.org/10.3390/ijms232214178 - 16 Nov 2022
Cited by 2 | Viewed by 1851
Abstract
With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands [...] Read more.
With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2′ ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors 15d and 15f exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors. Full article
(This article belongs to the Special Issue The Role of Protease Inhibitors in Infectious Diseases)
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