Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development

Zongyang Lv; Kristin E. Cano; Lijia Jia; Marcin Drag; Tony T. Huang; Shaun K. Olsen

doi:10.3389/fchem.2021.819165

journal article Open Access Feb 03, 2022

Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development

Zongyang Lv Kristin E. Cano

Lijia Jia Marcin Drag

Tony T. Huang Shaun K. Olsen

Frontiers in Chemistry Vol. 9 · Frontiers Media SA

View at Publisher Save 10.3389/fchem.2021.819165

Abstract

The emergence of severe acute respiratory syndrome (SARS-CoV-2) in 2019 marked the third occurrence of a highly pathogenic coronavirus in the human population since 2003. As the death toll surpasses 5 million globally and economic losses continue, designing drugs that could curtail infection and disease progression is critical. In the US, three highly effective Food and Drug Administration (FDA)–authorized vaccines are currently available, and Remdesivir is approved for the treatment of hospitalized patients. However, moderate vaccination rates and the sustained evolution of new viral variants necessitate the ongoing search for new antivirals. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation, and suppression of host innate immune responses. Knowledge of inhibitors and assays for viruses were quickly adopted for SARS-CoV-2 protease research. Potential candidates have been identified to show inhibitory effects against PLpro and Mpro, both in biochemical assays and viral replication in cells. These results encourage further optimizations to improve prophylactic and therapeutic efficacy. In this review, we examine the latest developments of potential small-molecule inhibitors and peptide inhibitors for PLpro and Mpro, and how structural biology greatly facilitates this process.

Topics

No keywords indexed for this article. Browse by subject →

References

135

[1]

Ahmad "Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations" Int. J. Mol. Sci. (2021) 10.3390/ijms22179124

[2]

Amamuddy "Impact of Early Pandemic Stage Mutations on Molecular Dynamics of SARS-CoV-2 Mpro" J. Chem. Inf. Model. (2020) 10.1021/acs.jcim.0c00634

[3]

Amin "Protease Targeted COVID-19 Drug Discovery and its Challenges: Insight into Viral Main Protease (Mpro) and Papain-like Protease (PLpro) Inhibitors" Bioorg. Med. Chem. (2021) 10.1016/j.bmc.2020.115860

[4]

Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives

Kangsa Amporndanai, Xiaoli Meng, Weijuan Shang et al.

Nature Communications 2021 10.1038/s41467-021-23313-7

[5]

Coronavirus Main Proteinase (3CL pro ) Structure: Basis for Design of Anti-SARS Drugs

Kanchan Anand, John Ziebuhr, Parvesh Wadhwani et al.

Science 2003 10.1126/science.1085658

[6]

Anders "Mechanism of the Metabolism of 1,3-benzodioxoles to Carbon Monoxide" Biochem. Pharmacol. (1984) 10.1016/0006-2952(84)90310-1

[7]

Azad "Ebselen, a Promising Antioxidant Drug: Mechanisms of Action and Targets of Biological Pathways" Mol. Biol. Rep. (2014) 10.1007/s11033-014-3417-x

[8]

Báez-Santos "X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases" J. Med. Chem. (2014) 10.1021/jm401712t

[9]

Báez-Santos "X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases" J. Med. Chem. (2014) 10.1021/jm401712t

[10]

Báez-Santos "Catalytic Function and Substrate Specificity of the Papain-like Protease Domain of Nsp3 from the Middle East Respiratory Syndrome Coronavirus" J. Virol. (2014) 10.1128/jvi.01294-14

[11]

The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds

Yahira M. Baez-Santos, Sarah E. St. John, Andrew D. Mesecar

Antiviral Research 2015 10.1016/j.antiviral.2014.12.015

[12]

Banerjee "Potential SARS-CoV-2 Main Protease Inhibitors" Drug Discov. Today (2021) 10.1016/j.drudis.2020.12.005

[13]

The Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus Has Deubiquitinating Activity

Naina Barretto, Dalia Jukneliene, Kiira Ratia et al.

Journal of Virology 2005 10.1128/jvi.79.24.15189-15198.2005

[14]

Baum "REGN-COV2 Antibodies Prevent and Treat SARS-CoV-2 Infection in Rhesus Macaques and Hamsters" Science (2020) 10.1126/science.abe2402

[15]

Bayoumy "The Continuous Rediscovery and the Benefit-Risk Ratio of Thioguanine, a Comprehensive Review" Expert Opin. Drug Metab. Toxicol. (2020) 10.1080/17425255.2020.1719996

[16]

Remdesivir for the Treatment of Covid-19 — Final Report

John H. Beigel, Kay M. Tomashek, Lori E. Dodd et al.

New England Journal of Medicine 2020 10.1056/nejmoa2007764

[17]

Békés "Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease" Mol. Cel (2016) 10.1016/j.molcel.2016.04.016

[18]

Bestle "TMPRSS2 and Furin Are Both Essential for Proteolytic Activation of SARS-CoV-2 in Human Airway Cells" Life Sci. Alliance (2020) 10.26508/lsa.202000786

[19]

Bzówka "Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design" Int. J. Mol. Sci. (2020) 10.3390/ijms21093099

[20]

Chen "Only One Protomer Is Active in the Dimer of SARS 3C-like Proteinase" J. Biol. Chem. (2006) 10.1074/jbc.m510745200

[21]

Chen "Synergistic Inhibition of SARS-CoV-2 Replication Using Disulfiram/Ebselen and Remdesivir" ACS Pharmacol. Transl. Sci. (2021) 10.1021/acsptsci.1c00022

[22]

Cheng "Thiopurine Analogs and Mycophenolic Acid Synergistically Inhibit the Papain-like Protease of Middle East Respiratory Syndrome Coronavirus" Antiviral Res. (2015) 10.1016/j.antiviral.2014.12.011

[23]

Chou "Thiopurine Analogues Inhibit Papain-like Protease of Severe Acute Respiratory Syndrome Coronavirus" Biochem. Pharmacol. (2008) 10.1016/j.bcp.2008.01.005

[24]

Chou "Structural Basis for Catalysis and Ubiquitin Recognition by the Severe Acute Respiratory Syndrome Coronavirus Papain-like Protease" Acta Crystallogr. D Biol. Crystallogr. (2014) 10.1107/s1399004713031040

[25]

Citarella "SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors" Biomolecules (2021) 10.3390/biom11040607

[26]

Clasman "Decoupling deISGylating and Deubiquitinating Activities of the MERS Virus Papain-like Protease" Antiviral Res. (2020) 10.1016/j.antiviral.2019.104661

[27]

Cook "Structure of a Diubiquitin Conjugate and a Model for Interaction with Ubiquitin Conjugating Enzyme (E2)" J. Biol. Chem. (1992) 10.1016/s0021-9258(18)42026-1

[28]

Cross "Sequence Characterization and Molecular Modeling of Clinically Relevant Variants of the SARS-CoV-2 Main Protease" Biochemistry (2020) 10.1021/acs.biochem.0c00462

[29]

Daczkowski "Structural Insights into the Interaction of Coronavirus Papain-like Proteases and Interferon-Stimulated Gene Product 15 from Different Species" J. Mol. Biol. (2017) 10.1016/j.jmb.2017.04.011

[30]

Dai "Structure-based Design of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease" Science (2020) 10.1126/science.abb4489

[31]

Dementiev "Molecular Mechanism of Inhibition of Acid Ceramidase by Carmofur" J. Med. Chem. (2019) 10.1021/acs.jmedchem.8b01723

[32]

Deng "Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain" Cell (2000) 10.1016/s0092-8674(00)00126-4

[33]

Drag "Positional-scanning Fluorigenic Substrate Libraries Reveal Unexpected Specificity Determinants of DUBs (Deubiquitinating Enzymes)" Biochem. J. (2008) 10.1042/bj20080779

[34]

Freitas "Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-like Protease" ACS Infect. Dis. (2020) 10.1021/acsinfecdis.0c00168

[35]

Fu "Both Boceprevir and GC376 Efficaciously Inhibit SARS-CoV-2 by Targeting its Main Protease" Nat. Commun. (2020) 10.1038/s41467-020-18233-x

[36]

Fu "The Complex Structure of GRL0617 and SARS-CoV-2 PLpro Reveals a Hot Spot for Antiviral Drug Discovery" Nat. Commun. (2021) 10.1038/s41467-020-20718-8

[37]

Gao "Crystal Structure of SARS-CoV-2 Papain-like Protease" Acta Pharmaceutica Sinica B (2021) 10.1016/j.apsb.2020.08.014

[38]

Ghosh "Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics" ChemMedChem (2020) 10.1002/cmdc.202000223

[39]

Ghosh "Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome−Coronavirus Papain-like Protease" J. Med. Chem. (2009) 10.1021/jm900611t

[40]

Ghosh "Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein−Ligand X-ray Structure and Biological Evaluation" J. Med. Chem. (2010) 10.1021/jm1004489

[41]

Giri "Understanding COVID-19 via Comparative Analysis of Dark Proteomes of SARS-CoV-2, Human SARS and Bat SARS-like Coronaviruses" Cell. Mol. Life Sci. (2021) 10.1007/s00018-020-03603-x

[42]

Goyal "Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy" ACS Comb. Sci. (2020) 10.1021/acscombsci.0c00058

[43]

Günther "X-ray Screening Identifies Active Site and Allosteric Inhibitors of SARS-CoV-2 Main Protease" Science (2021) 10.1126/science.abf7945

[44]

Gupta "Novel 2019-coronavirus on New Year's Eve" Indian J. Med. Microbiol. (2019) 10.4103/ijmm.ijmm_20_54

[45]

Halford "Pfizer Unveils its Oral SARS-CoV-2 Inhibitor" Chem. Eng. News (2021)

[46]

Identification of Severe Acute Respiratory Syndrome Coronavirus Replicase Products and Characterization of Papain-Like Protease Activity

Brian H. Harcourt, Dalia Jukneliene, Amornrat Kanjanahaluethai et al.

Journal of Virology 2004 10.1128/jvi.78.24.13600-13612.2004

[47]

Hayden "Shared Principles in NF-Κb Signaling" Cell (2008) 10.1016/j.cell.2008.01.020

[48]

Herold "A Human RNA Viral Cysteine Proteinase that Depends upon a Unique Zn2+-Binding finger Connecting the Two Domains of a Papain-like Fold" J. Biol. Chem. (1999) 10.1074/jbc.274.21.14918

[49]

Hilgenfeld "From SARS to MERS: Crystallographic Studies on Coronaviral Proteases Enable Antiviral Drug Design" Febs j (2014) 10.1111/febs.12936

[50]

Ho "Guideline on Management of Severe Acute Respiratory Syndrome (SARS)" The Lancet (2003) 10.1016/s0140-6736(03)13085-1

Showing 50 of 135 references

Cited By

80

Exploring potential SARS-CoV-2 Mpro non-covalent inhibitors through docking, pharmacophore profile matching, molecular dynamic simulation, and MM-GBSA

Yunfan Shi, Liting Dong · 2023

Journal of Molecular Modeling

Metrics

80

Citations

135

References

Details

Published: Feb 03, 2022
Vol/Issue: 9
License: View

Authors

Cite This Article

Zongyang Lv, Kristin E. Cano, Lijia Jia, et al. (2022). Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development. Frontiers in Chemistry, 9. https://doi.org/10.3389/fchem.2021.819165

Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development

You May Also Like