Structure-based design of SARS-CoV-2 papain-like protease inhibitors

Jadhav, Prakash; Huang, Bo; Osipiuk, Jerzy; Zhang, Xiaoming; Tan, Haozhou; Tesar, Christine; Endres, Michael; Jedrzejczak, Robert; Tan, Bin; Deng, Xufang; Joachimiak, Andrzej; Cai, Jianfeng; Wang, Jun

doi:10.1016/j.ejmech.2023.116011

Structure-based design of SARS-CoV-2 papain-like protease inhibitors

Journal Article · Tue Dec 05 00:00:00 EST 2023 · European Journal of Medicinal Chemistry

DOI:https://doi.org/10.1016/j.ejmech.2023.116011· OSTI ID:2368854

Jadhav, Prakash ^[1]; Huang, Bo ^[2]; Osipiuk, Jerzy ^[3]; Zhang, Xiaoming ^[4]; Tan, Haozhou ^[1]; Tesar, Christine ^[5]; Endres, Michael ^[5]; Jedrzejczak, Robert ^[5]; Tan, Bin ^[1]; Deng, Xufang ^[4]; Joachimiak, Andrzej ^[5]; Cai, Jianfeng ^[2]; ^[1]

State Univ. of New Jersey, Piscataway, NJ (United States)
Univ. of South Florida, Tampa, FL (United States)
Argonne National Laboratory (ANL), Argonne, IL (United States)
Oklahoma State Univ., Stillwater, OK (United States)
Argonne National Laboratory (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States)

The COVID-19 pandemic is caused by SARS-CoV-2, an RNA virus with high transmissibility and mutation rate. Given the paucity of orally bioavailable antiviral drugs to combat SARS-CoV-2 infection, there is a critical need for additional antivirals with alternative mechanisms of action. Papain-like protease (PL^pro) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PL^pro cleaves at three sites of the viral polyproteins. In addition, PLpro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PL^pro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PL^pro) with two potent inhibitors, Jun9722 and Jun9843. Subsequently, we designed and synthesized several series of analogs to explore the structure-activity relationship, which led to the discovery of PL^pro inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2368854

Alternate ID(s):: OSTI ID: 2229165

Journal Information:: European Journal of Medicinal Chemistry, Journal Name: European Journal of Medicinal Chemistry Vol. 264; ISSN 0223-5234

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (48)

Prevalence of Low-Frequency, Antiviral Resistance Variants in SARS-CoV-2 Isolates in Ontario, Canada, 2020-2023 Sjaarda, Calvin P.; Lau, Lynette; Simpson, Jared T. JAMA Network Open, Vol. 6, Issue 7 https://doi.org/10.1001/jamanetworkopen.2023.24963	journal	July 2023
Identification of Cysteine 270 as a Novel Site for Allosteric Modulators of SARS‐CoV‐2 Papain‐Like Protease** Hu, Hangchen; Wang, Qian; Su, Haixia Angewandte Chemie International Edition, Vol. 61, Issue 52 https://doi.org/10.1002/anie.202212378	journal	November 2022
SARS‐CoV‐2 Papain‐Like Protease: Structure, Function and Inhibition Ullrich, Sven; Nitsche, Christoph ChemBioChem, Vol. 23, Issue 19 https://doi.org/10.1002/cbic.202200327	journal	September 2022
Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics Ghosh, Arun K.; Brindisi, Margherita; Shahabi, Dana ChemMedChem, Vol. 15, Issue 11 https://doi.org/10.1002/cmdc.202000223	journal	May 2020
Protein Production for Structural Genomics Using E. coli Expression Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia Structural Genomics and Drug Discovery https://doi.org/10.1007/978-1-4939-0354-2_7	book	January 2014
Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor Tan, Haozhou; Ma, Chunlong; Wang, Jun Medicinal Chemistry Research, Vol. 31, Issue 7 https://doi.org/10.1007/s00044-022-02903-0	journal	May 2022
The history, mechanism, and perspectives of nirmatrelvir (PF-07321332): an orally bioavailable main protease inhibitor used in combination with ritonavir to reduce COVID-19-related hospitalizations Joyce, Ryan P.; Hu, Vivian W.; Wang, Jun Medicinal Chemistry Research, Vol. 31, Issue 10 https://doi.org/10.1007/s00044-022-02951-6	journal	August 2022
Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial Ader, Florence; Bouscambert-Duchamp, Maude; Hites, Maya The Lancet Infectious Diseases, Vol. 22, Issue 2 https://doi.org/10.1016/S1473-3099(21)00485-0	journal	February 2022
The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds Báez-Santos, Yahira M.; St. John, Sarah E.; Mesecar, Andrew D. Antiviral Research, Vol. 115 https://doi.org/10.1016/j.antiviral.2014.12.015	journal	March 2015
Chalcone-amide, a privileged backbone for the design and development of selective SARS-CoV/SARS-CoV-2 papain-like protease inhibitors Valipour, Mehdi European Journal of Medicinal Chemistry, Vol. 240 https://doi.org/10.1016/j.ejmech.2022.114572	journal	October 2022
Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review Li, Xin; Song, Yongcheng European Journal of Medicinal Chemistry, Vol. 260 https://doi.org/10.1016/j.ejmech.2023.115772	journal	November 2023
SARS-CoV-2 Main Protease Drug Design, Assay Development, and Drug Resistance Studies Tan, Bin; Joyce, Ryan; Tan, Haozhou Accounts of Chemical Research, Vol. 56, Issue 2 https://doi.org/10.1021/acs.accounts.2c00735	journal	December 2022
Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity Shen, Zhengnan; Ratia, Kiira; Cooper, Laura Journal of Medicinal Chemistry, Vol. 65, Issue 4 https://doi.org/10.1021/acs.jmedchem.1c01307	journal	October 2021
Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease Tan, Haozhou; Hu, Yanmei; Jadhav, Prakash Journal of Medicinal Chemistry, Vol. 65, Issue 11 https://doi.org/10.1021/acs.jmedchem.2c00303	journal	May 2022
Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay Ma, Chunlong; Sacco, Michael Dominic; Xia, Zilei ACS Central Science, Vol. 7, Issue 7 https://doi.org/10.1021/acscentsci.1c00519	journal	June 2021
Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir Hu, Yanmei; Lewandowski, Eric M.; Tan, Haozhou ACS Central Science https://doi.org/10.1021/acscentsci.3c00538	journal	July 2023
Drug-Repurposing Screening Identified Tropifexor as a SARS-CoV-2 Papain-like Protease Inhibitor Ma, Chunlong; Hu, Yanmei; Wang, Yuyin ACS Infectious Diseases, Vol. 8, Issue 5 https://doi.org/10.1021/acsinfecdis.1c00629	journal	April 2022
Validation and Invalidation of SARS-CoV-2 Papain-like Protease Inhibitors Ma, Chunlong; Wang, Jun ACS Pharmacology & Translational Science, Vol. 5, Issue 2 https://doi.org/10.1021/acsptsci.1c00240	journal	January 2022
Neutral red uptake assay for the estimation of cell viability/cytotoxicity Repetto, Guillermo; del Peso, Ana; Zurita, Jorge L. Nature Protocols, Vol. 3, Issue 7 https://doi.org/10.1038/nprot.2008.75	journal	June 2008
The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery Fu, Ziyang; Huang, Bin; Tang, Jinle Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-020-20718-8	journal	January 2021
Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors Osipiuk, Jerzy; Azizi, Saara-Anne; Dvorkin, Steve Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21060-3	journal	February 2021
De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report Gandhi, Shiv; Klein, Jonathan; Robertson, Alexander J. Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-29104-y	journal	March 2022
Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2 Sanders, Brian C.; Pokhrel, Suman; Labbe, Audrey D. Nature Communications, Vol. 14, Issue 1 https://doi.org/10.1038/s41467-023-37254-w	journal	March 2023
Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin Wydorski, Pawel M.; Osipiuk, Jerzy; Lanham, Benjamin T. Nature Communications, Vol. 14, Issue 1 https://doi.org/10.1038/s41467-023-38031-5	journal	April 2023
Therapeutic strategies for COVID-19: progress and lessons learned Li, Guangdi; Hilgenfeld, Rolf; Whitley, Richard Nature Reviews Drug Discovery, Vol. 22, Issue 6 https://doi.org/10.1038/s41573-023-00672-y	journal	April 2023
Characteristics of SARS-CoV-2 and COVID-19 Hu, Ben; Guo, Hua; Zhou, Peng Nature Reviews Microbiology, Vol. 19, Issue 3 https://doi.org/10.1038/s41579-020-00459-7	journal	October 2020
Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir Iketani, Sho; Mohri, Hiroshi; Culbertson, Bruce Nature, Vol. 613, Issue 7944 https://doi.org/10.1038/s41586-022-05514-2	journal	November 2022
Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis Kabinger, Florian; Stiller, Carina; Schmitzová, Jana Nature Structural & Molecular Biology, Vol. 28, Issue 9 https://doi.org/10.1038/s41594-021-00651-0	journal	August 2021
Remdesivir for the Treatment of Covid-19 — Final Report Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E. New England Journal of Medicine, Vol. 383, Issue 19 https://doi.org/10.1056/NEJMoa2007764	journal	November 2020
Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results Pan, Hongchao; Peto, Richard; Karim, Quarraisha Abdool New England Journal of Medicine, Vol. 384, Issue 6, p. 497-511 https://doi.org/10.1056/NEJMoa2023184	journal	February 2021
Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients Gottlieb, Robert L.; Vaca, Carlos E.; Paredes, Roger New England Journal of Medicine, Vol. 386, Issue 4 https://doi.org/10.1056/NEJMoa2116846	journal	January 2022
A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication Ratia, K.; Pegan, S.; Takayama, J. Proceedings of the National Academy of Sciences, Vol. 105, Issue 42 https://doi.org/10.1073/pnas.0805240105	journal	October 2008
Nirmatrelvir Resistance—de Novo E166V/L50V Mutations in an Immunocompromised Patient Treated With Prolonged Nirmatrelvir/Ritonavir Monotherapy Leading to Clinical and Virological Treatment Failure—a Case Report Zuckerman, Neta S.; Bucris, Efrat; Keidar-Friedman, Danielle Clinical Infectious Diseases https://doi.org/10.1093/cid/ciad494	journal	August 2023
β-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells Zhou, Shuntai; Hill, Collin S.; Sarkar, Sanjay The Journal of Infectious Diseases, Vol. 224, Issue 3 https://doi.org/10.1093/infdis/jiab247	journal	May 2021
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes Minor, Wladek; Cymborowski, Marcin; Otwinowski, Zbyszek Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8 https://doi.org/10.1107/S0907444906019949	journal	July 2006
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Molecular replacement with MOLREP Vagin, Alexei; Teplyakov, Alexei Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042589	journal	December 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
The CCP4 suite programs for protein crystallography No authors listed Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 5, p. 760-763 https://doi.org/10.1107/S0907444994003112	journal	September 1994
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design Rut, Wioletta; Lv, Zongyang; Zmudzinski, Mikolaj Science Advances, Vol. 6, Issue 42 https://doi.org/10.1126/sciadv.abd4596	journal	October 2020
An oral SARS-CoV-2 M ^pro inhibitor clinical candidate for the treatment of COVID-19 Owen, Dafydd R.; Allerton, Charlotte M. N.; Anderson, Annaliesa S. Science, Vol. 374, Issue 6575 https://doi.org/10.1126/science.abl4784	journal	December 2021
Approved Antiviral Drugs over the Past 50 Years De Clercq, Erik; Li, Guangdi Clinical Microbiology Reviews, Vol. 29, Issue 3 https://doi.org/10.1128/CMR.00102-15	journal	June 2016
SARS-CoV-2 Antiviral Therapy Tao, Kaiming; Tzou, Philip L.; Nouhin, Janin Clinical Microbiology Reviews, Vol. 34, Issue 4 https://doi.org/10.1128/CMR.00109-21	journal	December 2021
New Perspectives on Antimicrobial Agents: Molnupiravir and Nirmatrelvir/Ritonavir for Treatment of COVID-19 Atmar, Robert L.; Finch, Natalie Antimicrobial Agents and Chemotherapy, Vol. 66, Issue 8 https://doi.org/10.1128/aac.02404-21	journal	August 2022
Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2 Klemm, Theresa; Ebert, Gregor; Calleja, Dale J. The EMBO Journal, Vol. 39, Issue 18 https://doi.org/10.15252/embj.2020106275	journal	August 2020
Potential Inhibitors Targeting Papain-Like Protease of SARS-CoV-2: Two Birds With One Stone Jiang, Haihai; Yang, Peiyao; Zhang, Jin Frontiers in Chemistry, Vol. 10 https://doi.org/10.3389/fchem.2022.822785	journal	February 2022

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