Development of the Safe and Broad‐Spectrum Aldehyde and Ketoamide Mpro inhibitors Derived from the Constrained α, γ‐AA Peptide Scaffold

Wang, Lei; Ma, Chunlong; Sacco, Michael Dominic; Xue, Songyi; Mahmoud, Mentalla; Calcul, Laurent; Chen, Yu; Wang, Jun; Cai, Jianfeng

doi:10.1002/chem.202300476

Development of the Safe and Broad‐Spectrum Aldehyde and Ketoamide Mpro inhibitors Derived from the Constrained α, γ‐AA Peptide Scaffold

Journal Article · Fri May 05 04:00:00 UTC 2023 · Chemistry - A European Journal

DOI:https://doi.org/10.1002/chem.202300476· OSTI ID:2423380

Wang, Lei ^[1]; Ma, Chunlong ^[2]; Sacco, Michael Dominic ^[3]; Xue, Songyi ^[1]; Mahmoud, Mentalla ^[1]; Calcul, Laurent ^[1]; ^[3]; ^[4]; ^[1]

Department of Chemistry University of South Florida 4202 E. Fowler Ave. Tampa FL 33620 USA
Department of Pharmacology and Toxicology College of Pharmacy University of Arizona Tucson Arizona 85721 USA
Department of Molecular Medicine Morsani College of Medicine University of South Florida 4202 E. Fowler Ave. Tampa FL 33620 USA
Department of Pharmacology and Toxicology College of Pharmacy University of Arizona Tucson Arizona 85721 USA; Department of Medicinal Chemistry Ernest Mario School of Pharmacy, Rutgers University of New Jersey Piscataway NJ USA

Abstract

SARS‐CoV‐2 is still wreaking havoc all over the world with surging morbidity and high mortality. The main protease (M^pro) is essential in the replication of SARS‐CoV‐2, enabling itself an active target for antiviral development. Herein, we reported the design and synthesis of a new class of peptidomimetics‐constrained α, γ‐AA peptides, based on which a series of aldehyde and ketoamide inhibitors of the M^proof SARS‐CoV‐2 were prepared. The lead compounds showed excellent inhibitory activity in the FRET‐based M^proenzymatic assay not only for the M^proof SARS‐CoV‐2 but also for SARS‐CoV and MERS‐CoV, along with HCoVs like HCoV‐OC43, HCoV‐229E, HCoV‐NL63 and HKU1. The X‐ray crystallographic results demonstrated that our compounds form a covalent bond with the catalytic Cys145. They also demonstrated effective antiviral activity against live SARS‐CoV‐2. Overall, the results suggest that α, γ‐AA peptide could be a promising molecular scaffold in designing novel M^proinhibitors of SARS‐CoV‐2 and other coronaviruses.

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE

DOE Contract Number:: AC02-06CH11357

OSTI ID:: 2423380

Journal Information:: Chemistry - A European Journal, Journal Name: Chemistry - A European Journal Journal Issue: 35 Vol. 29; ISSN 0947-6539

Publisher:: Wiley

Country of Publication:: United States

Language:: English

References (36)

Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants Tahir ul Qamar, Muhammad; Alqahtani, Safar M.; Alamri, Mubarak A. Journal of Pharmaceutical Analysis, Vol. 10, Issue 4 https://doi.org/10.1016/j.jpha.2020.03.009	journal	August 2020
Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir Xia, Zilei; Sacco, Michael; Hu, Yanmei ACS Pharmacology & Translational Science, Vol. 4, Issue 4 https://doi.org/10.1021/acsptsci.1c00099	journal	June 2021
Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease Fu, Lifeng; Ye, Fei; Feng, Yong Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-18233-x	journal	September 2020
A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein Xue, Songyi; Wang, Xinling; Wang, Lei Cell Discovery, Vol. 8, Issue 1 https://doi.org/10.1038/s41421-022-00455-6	journal	September 2022
The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease Ren, Zhilin; Yan, Liming; Zhang, Ning Protein & Cell, Vol. 4, Issue 4 https://doi.org/10.1007/s13238-013-2841-3	journal	April 2013
A pneumonia outbreak associated with a new coronavirus of probable bat origin Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang Nature, Vol. 579, Issue 7798 https://doi.org/10.1038/s41586-020-2012-7	journal	February 2020
Recent development of 3C and 3CL protease inhibitors for anti-coronavirus and anti-picornavirus drug discovery Ramajayam, R.; Tan, Kian-Pin; Liang, Po-Huang Biochemical Society Transactions, Vol. 39, Issue 5 https://doi.org/10.1042/BST0391371	journal	September 2011
Dipyridamole, chloroquine, montelukast sodium, candesartan, oxytetracycline, and atazanavir are not SARS-CoV-2 main protease inhibitors Ma, Chunlong; Wang, Jun Proceedings of the National Academy of Sciences, Vol. 118, Issue 8 https://doi.org/10.1073/pnas.2024420118	journal	February 2021
Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease Ma, Chunlong; Sacco, Michael Dominic; Hurst, Brett Cell Research, Vol. 30, Issue 8 https://doi.org/10.1038/s41422-020-0356-z	journal	June 2020
Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease Dai, Wenhao; Zhang, Bing; Jiang, Xia-Ming Science, Vol. 368, Issue 6497 https://doi.org/10.1126/science.abb4489	journal	April 2020
Current status of antivirals and druggable targets of SARS CoV-2 and other human pathogenic coronaviruses Artese, Anna; Svicher, Valentina; Costa, Giosuè Drug Resistance Updates, Vol. 53 https://doi.org/10.1016/j.drup.2020.100721	journal	December 2020
SARS-CoV-2 M ^pro inhibitors with antiviral activity in a transgenic mouse model Qiao, Jingxin; Li, Yue-Shan; Zeng, Rui Science, Vol. 371, Issue 6536 https://doi.org/10.1126/science.abf1611	journal	February 2021
α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment Zhang, Linlin; Lin, Daizong; Kusov, Yuri Journal of Medicinal Chemistry, Vol. 63, Issue 9 https://doi.org/10.1021/acs.jmedchem.9b01828	journal	February 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
Covid-19: Is a second wave hitting Europe? Looi, Mun-Keat BMJ https://doi.org/10.1136/bmj.m4113	journal	October 2020
A new coronavirus associated with human respiratory disease in China Wu, Fan; Zhao, Su; Yu, Bin Nature, Vol. 579, Issue 7798 https://doi.org/10.1038/s41586-020-2008-3	journal	February 2020
Modulating Angiogenesis by Proteomimetics of Vascular Endothelial Growth Factor Abdulkadir, Sami; Li, Chunpu; Jiang, Wei Journal of the American Chemical Society, Vol. 144, Issue 1 https://doi.org/10.1021/jacs.1c09571	journal	December 2021
Non-covalent SARS-CoV-2 Mpro inhibitors developed from in silico screen hits Rossetti, Giacomo G.; Ossorio, Marianna A.; Rempel, Stephan Scientific Reports, Vol. 12, Issue 1 https://doi.org/10.1038/s41598-022-06306-4	journal	February 2022
The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor Yang, H.; Yang, M.; Ding, Y. Proceedings of the National Academy of Sciences, Vol. 100, Issue 23 https://doi.org/10.1073/pnas.1835675100	journal	October 2003
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
Sulfono-γ-AApeptides as Helical Mimetics: Crystal Structures and Applications Sang, Peng; Shi, Yan; Huang, Bo Accounts of Chemical Research, Vol. 53, Issue 10 https://doi.org/10.1021/acs.accounts.0c00482	journal	September 2020
Discovery of Cyclic Peptidomimetic Ligands Targeting the Extracellular Domain of EGFR Zheng, Mengmeng; Li, Chunpu; Zhou, Mi Journal of Medicinal Chemistry, Vol. 64, Issue 15 https://doi.org/10.1021/acs.jmedchem.1c00607	journal	July 2021
Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays Ma, Chunlong; Tan, Haozhou; Choza, Juliana Acta Pharmaceutica Sinica B, Vol. 12, Issue 4 https://doi.org/10.1016/j.apsb.2021.10.026	journal	April 2022
Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors Zhang, Linlin; Lin, Daizong; Sun, Xinyuanyuan Science https://doi.org/10.1126/science.abb3405	journal	March 2020
The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1 Sang, Peng; Zhou, Zhihong; Shi, Yan Science Advances, Vol. 6, Issue 20 https://doi.org/10.1126/sciadv.aaz4988	journal	May 2020
Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity Ma, Chunlong; Xia, Zilei; Sacco, Michael Dominic Journal of the American Chemical Society, Vol. 143, Issue 49 https://doi.org/10.1021/jacs.1c08060	journal	December 2021
Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs Anand, K. Science, Vol. 300, Issue 5626 https://doi.org/10.1126/science.1085658	journal	June 2003
Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses Su, Shuo; Wong, Gary; Shi, Weifeng Trends in Microbiology, Vol. 24, Issue 6 https://doi.org/10.1016/j.tim.2016.03.003	journal	June 2016
Boceprevir, Calpain Inhibitors II and XII, and GC-376 Have Broad-Spectrum Antiviral Activity against Coronaviruses Hu, Yanmei; Ma, Chunlong; Szeto, Tommy ACS Infectious Diseases, Vol. 7, Issue 3 https://doi.org/10.1021/acsinfecdis.0c00761	journal	March 2021
The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition Sacco, Michael Dominic; Hu, Yanmei; Gongora, Maura Verenice Cell Research, Vol. 32, Issue 5 https://doi.org/10.1038/s41422-022-00640-y	journal	March 2022
Sulfono‐γ‐AApeptides as Protein Helical Domain Mimetics to Manipulate the Angiogenesis Xue, Songyi; Wang, Lei; Cai, Jianfeng ChemBioChem, Vol. 23, Issue 22 https://doi.org/10.1002/cbic.202200298	journal	September 2022
Covid-19 in Australia: most infected health workers in Victoria’s second wave acquired virus at work Smith, Paul BMJ https://doi.org/10.1136/bmj.m3350	journal	August 2020
Challenges for Targeting SARS-CoV-2 Proteases as a Therapeutic Strategy for COVID-19 Steuten, Kas; Kim, Heeyoung; Widen, John C. ACS Infectious Diseases, Vol. 7, Issue 6 https://doi.org/10.1021/acsinfecdis.0c00815	journal	February 2021
Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M ^pro and cathepsin L Sacco, Michael Dominic; Ma, Chunlong; Lagarias, Panagiotis Science Advances, Vol. 6, Issue 50 https://doi.org/10.1126/sciadv.abe0751	journal	November 2020
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
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

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