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Coronaviruses

A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

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Article: 2246594 | Received 24 May 2023, Accepted 06 Aug 2023, Published online: 23 Aug 2023

References

  • Callaway E. Heavily mutated coronavirus variant puts scientists on alert. Nature. 2021;600(7887):21–21. doi:10.1038/D41586-021-03552-W
  • Planas D, Saunders N, Maes P, et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2022;602:671–675. doi:10.1038/s41586-021-04389-z
  • Takashita E, Yamayoshi S, Simon V, et al. Efficacy of antibodies and antiviral drugs against omicron BA.2.12.1, BA.4, and BA.5 subvariants. N Engl J Med. 2022;387:468–470. doi:10.1056/NEJMc2207519
  • Miller J, Hachmann NP, Collier AY, et al. Substantial neutralization escape by SARS-CoV-2 Omicron variants BQ.1.1 and XBB.1. N Engl J Med. 2023;388:662–664. doi:10.1056/NEJMc2214314
  • Holmes JA, Rutledge SM, Chung RT. Direct-acting antiviral treatment for hepatitis C. Lancet. 2019;393:1392–1394. doi:10.1016/S0140-6736(18)32326-2
  • Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006;194:11–19. doi:10.1086/505147
  • Chitalia VC, Munawar AH. A painful lesson from the COVID-19 pandemic: the need for broad-spectrum, host-directed antivirals. J Transl Med. 2020;18:390. doi:10.1186/s12967-020-02476-9
  • Murgolo N, Therien AG, Howell B, et al. SARS-CoV-2 tropism, entry, replication, and propagation: considerations for drug discovery and development. PLoS Pathog. 2021;17:e1009225. doi:10.1371/journal.ppat.1009225
  • Shagufta AI. The race to treat COVID-19: potential therapeutic agents for the prevention and treatment of SARS-CoV-2. Eur J Med Chem. 2021;213:113157. doi:10.1016/j.ejmech.2021.113157
  • Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 – final report. N Engl J Med. 2020;383:1813–1826. doi:10.1056/NEJMoa2007764
  • Arch B, Kovacs D, Scott J, et al. Evaluation of the effectiveness of remdesivir in treating severe COVID-19 using data from the ISARIC WHO clinical characterisation protocol UK: a prospective, national cohort study. medRxiv. 2021; 2021.06.18.21259072.
  • Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374:1586–1593. doi:10.1126/science.abl4784
  • Ledford H, Maxmen A. African clinical trial denied access to key COVID drug Paxlovid. Nature. 2022;604:412–413. doi:10.1038/d41586-022-01069-4
  • Bartlett JA, DeMasi R, Quinn J, et al. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS. 2001;15:1369–1377. doi:10.1097/00002030-200107270-00006
  • Hussain M, Galvin HD, Haw TY, et al. Drug resistance in influenza A virus: the epidemiology and management. Infect Drug Resist. 2017;10:121–134. doi:10.2147/IDR.S105473
  • Stanciu C, Muzica CM, Girleanu I, et al. An update on direct antiviral agents for the treatment of hepatitis C. Expert Opin Pharmacother. 2021;22:1729–1741. doi:10.1080/14656566.2021.1921737
  • Jochmans D, Liu C, Donckers K, et al. The substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir. mBio. 2023. doi:10.1128/MBIO.02815-22/SUPPL_FILE/MBIO.02815-22-S0004.DOCX
  • Ranganath N, O’Horo JC, Challener DW, et al. Rebound phenomenon after nirmatrelvir/ritonavir treatment of coronavirus disease-2019 in high-risk persons. Clin Infect Dis. 2023;76:e537–e539. doi:10.1093/cid/ciac481
  • Ip JD, Wing-Ho Chu A, Chan W-M, et al. Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance. EBioMedicine. 2023;91:104559. doi:10.1016/j.ebiom.2023.104559
  • Mody V, Ho J, Wills S, et al. Identification of 3-chymotrypsin like protease (3CLpro) inhibitors as potential anti-SARS-CoV-2 agents. Communications Biol. 2021;4(1):1–10. doi:10.1038/s42003-020-01566-0
  • Shi J, Wei Z, Song J. Dissection study on the severe acute respiratory syndrome 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme: defining the extra domain as a new target for design of highly specific protease inhibitors*. J Biol Chem. 2004;279:24765–24773. doi:10.1074/jbc.M311744200
  • Silvestrini L, Belhaj N, Comez L, et al. The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors. Sci Rep. 2021;11:1–16. doi:10.1038/s41598-020-79139-8
  • Anand K, Ziebuhr J, Wadhwani P, et al. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science. 2003;300:1763–1767. doi:10.1126/science.1085658
  • Yang H, Yang M, Ding Y, et al. The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc Natl Acad Sci USA. 2003;100:13190–13195. doi:10.1073/pnas.1835675100
  • Xue X, Yu H, Yang H, et al. Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design. J Virol. 2008;82:2515–2527. doi:10.1128/JVI.02114-07
  • Kneller DW, Phillips G, O’Neill HM, et al. Structural plasticity of SARS-CoV-2 3CL Mpro active site cavity revealed by room temperature X-ray crystallography. Nat Commun. 2020;11(1):1–6. doi:10.1038/s41467-019-13872-1
  • Lee J, Worrall LJ, Vuckovic M, et al. Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site. Nat Commun. 2020;11:1–9. doi:10.1038/s41467-019-13993-7
  • Callaway E. Beyond Omicron: what’s next for COVID’s viral evolution. Nature. 2021;600:204–207. doi:10.1038/d41586-021-03619-8
  • Indari O, Jakhmola S, Manivannan E, et al. An update on antiviral therapy against SARS-CoV-2: how far have We come? Front Pharmacol. 2021;0:133.
  • Douangamath A, Fearon D, Gehrtz P, et al. Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease. Nat Commun. 2020;11:1–11. doi:10.1038/s41467-019-13993-7
  • Shapira T, Monreal IA, Dion SP, et al. A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature. 2022;605:340–348. doi:10.1038/s41586-022-04661-w
  • Pérez-Vargas J, Shapira T, Olmstead AD, et al. Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics. Antiviral Res. 2023;209:105484. doi:10.1016/j.antiviral.2022.105484
  • Tang J, Wennerberg K, Aittokallio T. What is synergy? The Saariselkä agreement revisited. Front Pharmacol. 2015;6:1–6. doi:10.3389/fphar.2015.00181
  • Yadav B, Wennerberg K, Aittokallio T, et al. Searching for drug synergy in complex dose–response landscapes using an interaction potency model. Comput Struct Biotechnol J. 2015;13:504–513. doi:10.1016/j.csbj.2015.09.001
  • Zheng S, Wang W, Aldahdooh J, et al. Synergyfinder plus: toward better interpretation and annotation of drug combination screening datasets. Genomics Proteomics Bioinformatics. 2022. doi:10.1016/j.gpb.2022.01.004
  • Sacco MD, Ma C, Lagarias P, et al. Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L. Sci Adv. 2020: 6. doi:10.1126/SCIADV.ABE0751
  • Hamill P, Hudson D, Kao RY, et al. Development of a red-shifted fluorescence-based assay for SARS-coronavirus 3CL protease: identification of a novel class of anti-SARS agents from the tropical marine sponge Axinella corrugata. Biol Chem. 2006;387:1063–1074. doi:10.1515/BC.2006.131
  • Meyer B, Chiaravalli J, Gellenoncourt S, et al. Characterising proteolysis during SARS-CoV-2 infection identifies viral cleavage sites and cellular targets with therapeutic potential. Nat Commun. 2021;12:1–16. doi:10.1038/s41467-020-20314-w
  • Jean F, Basak A, Dimaio J, et al. An internally quenched fluorogenic substrate of prohormone convertase 1 and furin leads to a potent prohormone convertase inhibitor. Biochem J. 1995;307:689–695. doi:10.1042/bj3070689
  • Yaron A, Carmel A, Katchalski-Katzir E. Intramolecularly quenched fluorogenic substrates for hydrolytic enzymes. Anal Biochem. 1979;95:228–235. doi:10.1016/0003-2697(79)90210-0
  • Froggatt HM, Heaton BE, Heaton NS. Development of a fluorescence-based, high-throughput SARS-CoV-2 3CLpro reporter assay. J Virol. 2020;94; doi:10.1128/JVI.01265-20
  • Citarella A, Scala A, Piperno A, et al. SARS-CoV-2 mpro: a potential target for peptidomimetics and small-molecule inhibitors. Biomolecules. 2021;11:607. doi:10.3390/biom11040607
  • Cons BD, Twigg DG, Kumar R, et al. Electrostatic complementarity in structure-based drug design. J Med Chem. 2022;65:7476–7488. doi:10.1021/acs.jmedchem.2c00164
  • Hou N, Shuai L, Zhang L, et al. Development of highly potent noncovalent inhibitors of SARS-CoV-2 3CLpro. ACS Cent Sci. 2022. doi:10.1021/ACSCENTSCI.2C01359/ASSET/IMAGES/LARGE/OC2C01359_0006.JPEG
  • Plante JA, Mitchell BM, Plante KS, et al. The variant gambit: COVID-19’s next move. Cell Host Microbe. 2021;29:508–515. doi:10.1016/j.chom.2021.02.020
  • Poutanen SM. Human Coronaviruses. Principles and Practice of Pediatric Infectious Diseases. 2012:1117–1120.e4. doi:10.1016/B978-1-4377-2702-9.00224-5.
  • Shitrit A, Zaidman D, Kalid O, et al. Conserved interactions required for inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sci Rep. 2020;10:20808. doi:10.1038/s41598-020-77794-5
  • Chang FY, Brady SF. Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening. Proc Natl Acad Sci USA. 2013;110:2478–2483. doi:10.1073/pnas.1222125110
  • Parums DV. Editorial: The XBB.1.5 (‘Kraken’) subvariant of Omicron SARS-CoV-2 and its rapid global spread. Med Sci Monit. 2023;29:e939580-1.
  • Lewnard JA, Hong V, Kim JS, et al. Increased vaccine sensitivity of an emerging SARS-CoV-2 variant. medRxiv. 2023. 2023.03.11.23287148.
  • Bowman EJ, Siebers A, Altendorf K. Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc Natl Acad Sci USA. 1988;85:7972–7976. doi:10.1073/pnas.85.21.7972
  • Greasley SE, Noell S, Plotnikova O, et al. Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants. J Biol Chem. 2022;298:101972. doi:10.1016/j.jbc.2022.101972
  • Drayman N, DeMarco JK, Jones KA, et al. Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2. Science. (1979) 2021;373:931–936. doi:10.1126/science.abg5827
  • Kim Y, Shivanna V, Narayanan S, et al. Broad-Spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses. J Virol. 2015;89:4942–4950. doi:10.1128/JVI.03688-14
  • Tzou PL, Tao K, Nouhin J, et al. Coronavirus antiviral research database (CoV-RDB): an online database designed to facilitate comparisons between candidate anti-coronavirus compounds. Viruses. 2020;12:1006. doi:10.3390/v12091006
  • Dampalla CS, Zheng J, Dinali Perera K, et al. Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection. Proc Natl Acad Sci USA. 2021. doi:10.1073/pnas.2101555118
  • Su H, Yao S, Zhao W, et al. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease. Nat Commun. 2021;12:1–12. doi:10.1038/s41467-020-20314-w
  • Singh J, Anantharaj A, Panwar A, et al. BA.1, BA.2 and BA.2.75 variants show comparable replication kinetics, reduced impact on epithelial barrier and elicit cross-neutralizing antibodies. PLoS Pathog. 2023;19:e1011196. doi:10.1371/journal.ppat.1011196
  • Li P, Wang Y, Lavrijsen M, et al. SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination. Cell Res. 2022;32:322–324. doi:10.1038/s41422-022-00618-w
  • Schultz DC, Johnson RM, Ayyanathan K, et al. Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2. Nature. 2022;604:134–140. doi:10.1038/s41586-022-04482-x