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Viruses
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Enzymes as Antiviral Targets
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Enzymes as Antiviral Targets

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 16587

Special Issue Editors

Dr. Eleftherios Michailidis

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Guest Editor
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Health Sciences Research Building, Atlanta, GA 30322, USA
Interests: hepatology; viral hepatitis; liver disease; innate immunity; antivirals
Prof. Dr. Stefan G. Sarafianos

E-Mail Website
Guest Editor
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Health Sciences Research Building, Atlanta, GA 30322, USA
Interests: viral replication and entry; antivirals; capsid protein; HIV
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viral enzymes have been the targets of antiviral strategies for several decades, which has informed drug development efforts that have resulted in effective therapeutics across multiple virus families. With the advancement of molecular virology, we have gained insights into the role of individual viral proteins in the replication cycle of targeted viruses. Among these proteins, the viral enzymes have been the core of multiple drug development programs. This is in part due to their specificity over host proteins as well as due to our ability to develop quantitative assays for drug screens. In addition, the revolution that has taken place in the fields of medicinal chemistry and computational molecular modeling has greatly enhanced our ability to develop very potent inhibitors that target viral enzymes. Examples of this success include the development of viral polymerase inhibitors that are now approved drugs against herpes virus (HSV-1), human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), hepatitis C virus (HCV), and more recently SARS-CoV-2. It is worth mentioning that the polymerase inhibitors against HCV not only suppress viral replication but also lead to a cure against this deadly virus. The introduction of HIV-1 protease inhibitors gave rise to the first successful combination therapies that led to life-changing therapeutic regimens and established multi-target combination antiviral strategies. With novel drug formulation and delivery approaches, long-acting antivirals that target viral proteins have also made a significant breakthrough in antiviral treatments. Together, these advances have positively impacted the course of epidemics and were able to prevent millions of deaths. The future seems even brighter as more viral proteins become targets of drug development programs and combination strategies achieve better barriers to resistance. In light of the ongoing COVID-19 pandemic, it is urgent to develop therapeutics that effectively fight viruses before and during the course of an epidemic or pandemic; towards this goal, viral enzymes have been the major targets.

In this Special Issue of Viruses, we aim to discuss the recent developments and breakthroughs of antivirals that target viral proteins, examining them at the molecular level with respect to special mechanisms of action and resistance, as well as exploring new methods of drug formulation, drug delivery, and toxicology profiles. With these goals in mind, we invite you to contribute your most recent research findings and insights with original research papers, technical advancements, or review articles.

Dr. Eleftherios Michailidis
Prof. Dr. Stefan G. Sarafianos
Guest Editors

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Published Papers (5 papers)

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Research

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17 pages, 2039 KiB  
Article
HIV-1 Resistance to Islatravir/Tenofovir Combination Therapy in Wild-Type or NRTI-Resistant Strains of Diverse HIV-1 Subtypes
by Maria E. Cilento, Xin Wen, Aaron B. Reeve, Obiaara B. Ukah, Alexa A. Snyder, Ciro M. Carrillo, Cole P. Smith, Kristin Edwards, Claudia C. Wahoski, Deborah R. Kitzler, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, Philip R. Tedbury and Stefan G. Sarafianos
Viruses 2023, 15(10), 1990; https://doi.org/10.3390/v15101990 - 25 Sep 2023
Cited by 2 | Viewed by 1989
Abstract
Tenofovir disoproxil fumarate (TDF) and islatravir (ISL, 4′-ethynyl-2-fluoro-2′-deoxyadensine, or MK-8591) are highly potent nucleoside reverse transcriptase inhibitors. Resistance to TDF and ISL is conferred by K65R and M184V, respectively. Furthermore, K65R and M184V increase sensitivity to ISL and TDF, respectively. Therefore, these two [...] Read more.
Tenofovir disoproxil fumarate (TDF) and islatravir (ISL, 4′-ethynyl-2-fluoro-2′-deoxyadensine, or MK-8591) are highly potent nucleoside reverse transcriptase inhibitors. Resistance to TDF and ISL is conferred by K65R and M184V, respectively. Furthermore, K65R and M184V increase sensitivity to ISL and TDF, respectively. Therefore, these two nucleoside analogs have opposing resistance profiles and could present a high genetic barrier to resistance. To explore resistance to TDF and ISL in combination, we performed passaging experiments with HIV-1 WT, K65R, or M184V in the presence of ISL and TDF. We identified K65R, M184V, and S68G/N mutations. The mutant most resistant to ISL was S68N/M184V, yet it remained susceptible to TDF. To further confirm our cellular findings, we implemented an endogenous reverse transcriptase assay to verify in vitro potency. To better understand the impact of these resistance mutations in the context of global infection, we determined potency of ISL and TDF against HIV subtypes A, B, C, D, and circulating recombinant forms (CRF) 01_AE and 02_AG with and without resistance mutations. In all isolates studied, we found K65R imparted hypersensitivity to ISL whereas M184V conferred resistance. We demonstrated that the S68G polymorphism can enhance fitness of drug-resistant mutants in some genetic backgrounds. Collectively, the data suggest that the opposing resistance profiles of ISL and TDF suggest that a combination of the two drugs could be a promising drug regimen for the treatment of patients infected with any HIV-1 subtype, including those who have failed 3TC/FTC-based therapies. Full article
(This article belongs to the Special Issue Enzymes as Antiviral Targets)
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15 pages, 2617 KiB  
Article
Analysis of Template Variations on RNA Synthesis by Respiratory Syncytial Virus Polymerase
by Dongdong Cao, Inesh Gooneratne, Cristopher Mera, Jenny Vy, Maurice Royal, Bozun Huang, Yuri Park, Ambika Manjunath and Bo Liang
Viruses 2023, 15(1), 47; https://doi.org/10.3390/v15010047 - 23 Dec 2022
Cited by 3 | Viewed by 2176
Abstract
Respiratory syncytial virus (RSV) is a significant threat to infants and elderly individuals globally. Currently, there are no effective therapies or treatments for RSV infection because of an insufficient understanding of the RSV viral machinery. In this study, we investigated the effects of [...] Read more.
Respiratory syncytial virus (RSV) is a significant threat to infants and elderly individuals globally. Currently, there are no effective therapies or treatments for RSV infection because of an insufficient understanding of the RSV viral machinery. In this study, we investigated the effects of the template variations on RNA synthesis by the RSV polymerase through in vitro RNA synthesis assays. We confirmed the previously reported back-priming activity of the RSV polymerase, which is likely due to the secondary structure of the RNA template. We found that the expansion of the hairpin loop size of the RNA template abolishes the RSV polymerase back-priming activity. At the same time, it seemingly does not affect the de novo RNA synthesis activities of the RSV polymerase. Interestingly, our results show that the RSV polymerase also has a new primer-based terminal extension activity that adds nucleotides to the template and primer in a nonspecific manner. We also mapped the impact of the RNA 5′ chemical group on its mobility in a urea-denaturing RNA gel shift assay. Overall, these results enhance our knowledge about the RNA synthesis processes of the RSV polymerase and may guide future therapeutic efforts to develop effective antiviral drugs for RSV treatment. Full article
(This article belongs to the Special Issue Enzymes as Antiviral Targets)
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6 pages, 6429 KiB  
Communication
Drug Interactions in Lenacapavir-Based Long-Acting Antiviral Combinations
by Maria E. Cilento, Yee Tsuey Ong, Philip R. Tedbury and Stefan G. Sarafianos
Viruses 2022, 14(6), 1202; https://doi.org/10.3390/v14061202 - 31 May 2022
Cited by 8 | Viewed by 3629
Abstract
Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV [...] Read more.
Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV agents such as lenacapavir (a capsid-targeting antiviral) and islatravir (EFdA, a nucleoside reverse transcriptase translocation inhibitor) need to be explored as combination therapies. Therefore, we sought to determine whether combination of lenacapavir with islatravir, rilpivirine, or cabotegravir displayed synergy, additivity, or antagonism. We performed dose-response matrices of these drug combinations in an HIV-1 reporter cell line and subsequently analyzed the data with SynergyFinder Plus, which employs four major drug interaction models: highest single agent, Bliss independence, Loewe additivity, and zero interaction potency. Most of these models predict additive inhibition by the studied drug combinations This work highlights the importance of effective drug combinations in LA-regimens. Full article
(This article belongs to the Special Issue Enzymes as Antiviral Targets)
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18 pages, 2260 KiB  
Article
Novel Compound Inhibitors of HIV-1NL4-3 Vpu
by Carolyn A. Robinson, Terri D. Lyddon, Hwi Min Gil, David T. Evans, Yury V. Kuzmichev, Jonathan Richard, Andrés Finzi, Sarah Welbourn, Lynn Rasmussen, N. Miranda Nebane, Vandana V. Gupta, Sam Ananthan, Zhaohui Cai, Elizabeth R. Wonderlich, Corinne E. Augelli-Szafran, Robert Bostwick, Roger G. Ptak, Susan M. Schader and Marc C. Johnson
Viruses 2022, 14(4), 817; https://doi.org/10.3390/v14040817 - 15 Apr 2022
Cited by 4 | Viewed by 3474
Abstract
HIV-1 Vpu targets the host cell proteins CD4 and BST-2/Tetherin for degradation, ultimately resulting in enhanced virus spread and host immune evasion. The discovery and characterization of small molecules that antagonize Vpu would further elucidate the contribution of Vpu to pathogenesis and lay [...] Read more.
HIV-1 Vpu targets the host cell proteins CD4 and BST-2/Tetherin for degradation, ultimately resulting in enhanced virus spread and host immune evasion. The discovery and characterization of small molecules that antagonize Vpu would further elucidate the contribution of Vpu to pathogenesis and lay the foundation for the study of a new class of novel HIV-1 therapeutics. To identify novel compounds that block Vpu activity, we have developed a cell-based ‘gain of function’ assay that produces a positive signal in response to Vpu inhibition. To develop this assay, we took advantage of the viral glycoprotein, GaLV Env. In the presence of Vpu, GaLV Env is not incorporated into viral particles, resulting in non-infectious virions. Vpu inhibition restores infectious particle production. Using this assay, a high throughput screen of >650,000 compounds was performed to identify inhibitors that block the biological activity of Vpu. From this screen, we identified several positive hits but focused on two compounds from one structural family, SRI-41897 and SRI-42371. We developed independent counter-screens for off target interactions of the compounds and found no off target interactions. Additionally, these compounds block Vpu-mediated modulation of CD4, BST-2/Tetherin and antibody dependent cell-mediated toxicity (ADCC). Unfortunately, both SRI-41897 and SRI-42371 were shown to be specific to the N-terminal region of NL4-3 Vpu and did not function against other, more clinically relevant, strains of Vpu; however, this assay may be slightly modified to include more significant Vpu strains in the future. Full article
(This article belongs to the Special Issue Enzymes as Antiviral Targets)
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Review

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10 pages, 609 KiB  
Review
Beyond Inhibition: A Novel Strategy of Targeting HIV-1 Protease to Eliminate Viral Reservoirs
by Josh G. Kim and Liang Shan
Viruses 2022, 14(6), 1179; https://doi.org/10.3390/v14061179 - 28 May 2022
Cited by 9 | Viewed by 3252
Abstract
HIV-1 protease (PR) is a viral enzyme that cleaves the Gag and Gag-Pol polyprotein precursors to convert them into their functional forms, a process which is essential to generate infectious viral particles. Due to its broad substrate specificity, HIV-1 PR can also cleave [...] Read more.
HIV-1 protease (PR) is a viral enzyme that cleaves the Gag and Gag-Pol polyprotein precursors to convert them into their functional forms, a process which is essential to generate infectious viral particles. Due to its broad substrate specificity, HIV-1 PR can also cleave certain host cell proteins. Several studies have identified host cell substrates of HIV-1 PR and described the potential impact of their cleavage on HIV-1-infected cells. Of particular interest is the interaction between PR and the caspase recruitment domain-containing protein 8 (CARD8) inflammasome. A recent study demonstrated that CARD8 can sense HIV-1 PR activity and induce cell death. While PR typically has low levels of intracellular activity prior to viral budding, premature PR activation can be achieved using certain non-nucleoside reverse transcriptase inhibitors (NNRTIs), resulting in CARD8 cleavage and downstream pyroptosis. Used together with latency reversal agents, the induction of premature PR activation to trigger CARD8-mediated cell killing may help eliminate latent reservoirs in people living with HIV. This represents a novel strategy of utilizing PR as an antiviral target through premature activation rather than inhibition. In this review, we discuss the viral and host substrates of HIV-1 protease and highlight potential applications and advantages of targeting CARD8 sensing of HIV-1 PR. Full article
(This article belongs to the Special Issue Enzymes as Antiviral Targets)
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