Preclinical discovery and development of nirmatrelvir/ritonavir combinational therapy for the treatment of COVID-19 and the lessons learned from SARS-COV-2 variants

References

• Suleyman G, Fadel R, Brar I, et al. Risk Factors associated with hospitalization and death in COVID-19 Breakthrough infections. Open Forum Infect Dis. 2022;9(5):ofac116. PMID: 35437511; PMCID: PMC8903475. doi: 10.1093/ofid/ofac116
   PubMed Web of Science ®Google Scholar
• Rosenberg ES, Holtgrave DR, Dorabawila V, et al. New COVID-19 cases and hospitalizations among adults, by vaccination status — new York, May 3–July 25, 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1306–1311. doi: 10.15585/mmwr.mm7037a7
   PubMedGoogle Scholar
• Pagliano P, Sellitto C, Conti V, et al. Characteristics of viral pneumonia in the COVID-19 era: an update. Infection. 2021;49(4):607–616. PMID: 33782861;PMCID: PMC8006879. doi: 10.1007/s15010-021-01603-y
   PubMed Web of Science ®Google Scholar
• Brouwer MC, Ascione T, Pagliano P. Neurologic aspects of covid-19: a concise review. Infez Med. 2020;28(suppl 1): 42–45. PMID: 32532937.
   PubMedGoogle Scholar
• El-Sadr WM, Vasan A, El-Mohandes A. Facing the new covid-19 Reality. N Engl J Med. 2023;388(5):385–387. PMID: 36724378. doi: 10.1056/NEJMp2213920
   PubMed Web of Science ®Google Scholar
• Karampitsakos T, Papaioannou O, Tsiri P, et al. Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label, randomized controlled trial. Clin Microbiol Infect. 2023;29(3):372–378. PMID: 36273769; PMCID: PMC9636985. doi: 10.1016/j.cmi.2022.10.015
   PubMed Web of Science ®Google Scholar
• Bellino S. COVID-19 treatments approved in the European Union and clinical recommendations for the management of non-hospitalized and hospitalized patients. Ann Med. 2022;54(1):2856–2860. PMID: 36259490; PMCID: PMC9586661. doi: 10.1080/07853890.2022.2133162
   PubMed Web of Science ®Google Scholar
• Pagliano P, Scarpati G, Sellitto C, et al. Experimental Pharmacotherapy for COVID-19: The Latest Advances. J Exp Pharmacol PMID: 33442304; PMCID: PMC7800714 2021 Jan 7;13:1–13. doi: 10.2147/JEP.S255209
   PubMedGoogle Scholar
• Pagliano P, Sellitto C, Scarpati G, et al. An overview of the preclinical discovery and development of remdesivir for the treatment of coronavirus disease 2019 (COVID-19). Expert Opin Drug Discov. 2022 Jan;17(1):9–18. Epub 2021 Aug 27. PMID: 34412564; PMCID: PMC8425432. doi: 10.1080/17460441.2021.1970743
   PubMed Web of Science ®Google Scholar
• Pagliano P, Sellitto C, Ascione T, et al. The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19). Expert Opin Drug Discov. 2022 Dec;17(12):1299–1311. Epub 2022 Dec 12. PMID: 36508255. doi: 10.1080/17460441.2022.2153828.
   PubMed Web of Science ®Google Scholar
• Rut W, Groborz K, Zhang L, et al. SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging. Nat Chem Biol. 2021 Feb;17(2):222–228. Epub 2020 Oct 22. PMID: 33093684. doi: 10.1038/s41589-020-00689-z
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Xia Z, Sacco M, Hu Y, et al. 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. ACS Pharmacol Transl Sci. 2021;4:1408–1421. doi: 10.1021/acsptsci.1c00099
   PubMedGoogle Scholar
• Focosi D, McConnell S, Shoham S, et al. Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics. Int J Antimicrob Agents. 2023 Feb;61(2):106708. Epub 2023 Jan 2. PMID: 36603694; PMCID: PMC9806926. doi: 10.1016/j.ijantimicag.2022.106708
   PubMed Web of Science ®Google Scholar
• Lamb YN. Nirmatrelvir Plus ritonavir: First Approval. Drugs. 2022 Apr;82(5):585–591. doi: 10.1007/s40265-022-01692-5
   PubMed Web of Science ®Google Scholar
• Chen W, Liang B, Wu X, et al. Advances and challenges in using nirmatrelvir and its derivatives against sars-Cov-2 infection. J Pharm Anal. 2023 Mar;13(3):255–261. Epub ahead of print. PMID: 36345404; PMCID: PMC9628234. doi: 10.1016/j.jpha.2022.10.005
   PubMed Web of Science ®Google Scholar
• Vandyck K, Deval J. Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection. Curr Opin Virol. 2021 Aug;49:36–40. Epub 2021 Apr 27. PMID: 34029993; PMCID: PMC8075814. doi: 10.1016/j.coviro.2021.04.006
   PubMed Web of Science ®Google Scholar
• Wen W, Chen C, Tang J, et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis. Ann Med. 2022 Dec;54(1):516–523. PMID: 35118917; PMCID: PMC8820829. doi: 10.1080/07853890.2022.2034936
   PubMed Web of Science ®Google Scholar
• Lee TC, Morris AM, Grover SA, et al. Outpatient therapies for COVID-19: how do we choose? Open Forum Infect Dis. 2022 Jan 19;9(3): ofac008. PMID: 35165657; PMCID: PMC8807279. doi: 10.1093/ofid/ofac008
   PubMedGoogle Scholar
• Mahase E. Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. 2021 Nov 8;375:n2713. PMID: 34750163. doi: 10.1136/bmj.n2713
   PubMedGoogle Scholar
• Majerová T, Konvalinka J. Viral proteases as therapeutic targets. Mol Aspects Med. 2022;88:101159. doi: 10.1016/j.mam.2022.101159
   PubMed Web of Science ®Google Scholar
• Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A. 2020;117(21):11727–11734. PMID: 32376634; PMCID: PMC7260975. doi: 10.1073/pnas.2003138117
   PubMed Web of Science ®Google Scholar
• Farady CJ, Craik CS. Mechanisms of macromolecular protease inhibitors. Chembiochem. 2010 Nov 22;11(17):2341–2346. PMID: 21053238; PMCID: PMC4150018 10.1002/cbic.201000442
   PubMed Web of Science ®Google Scholar
• Boras B, Jones RM, Anson BJ, et al. Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nat Commun. 2021;12(1):6055. doi: 10.1038/s41467-021-26239-2.
   PubMed Web of Science ®Google Scholar
• De Vries M, Mohamed AS, Prescott RA, et al. A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19. J Virol. 2021 Mar 10;95(10): e01819–20. Epub 2021 Feb 23. PMID: 33622961; PMCID: PMC8139662. doi: 10.1128/JVI.01819-20
   PubMed Web of Science ®Google Scholar
• Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022 Feb; 198:105252. doi: 10.1016/j.antiviral.2022.105252. Epub 2022 Jan 24. PMID: 35085683; PMCID: PMC8785409.
   PubMed Web of Science ®Google Scholar
• Vanhulle E, Stroobants J, Provinciael B, et al. SARS-CoV-2 Permissive glioblastoma cell line for high throughput antiviral screening. Antiviral Res. 2022 Jul;203:105342. Epub 2022 May 18. PMID: 35595082; PMCID: PMC9113983. doi: 10.1016/j.antiviral.2022.105342
   PubMed Web of Science ®Google Scholar
• Saleh MAA, Hirasawa M, Sun M, et al. The PBPK LeiCNS-PK3.0 framework predicts nirmatrelvir (but not remdesivir or molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells. Eur J Pharm Sci Epub 2022 Nov 30. PMID: 36462547; PMCID: PMC9710098 2023 Feb 1;181:106345. doi: 10.1016/j.ejps.2022.106345
   PubMed Web of Science ®Google Scholar
• Iketani S, Mohri H, Culbertson B, et al. Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir. Nature. 2023 Jan;613(7944):558–564. Epub 2022 Nov 9. PMID: 36351451; PMCID: PMC9849135. doi: 10.1038/s41586-022-05514-2
   PubMed Web of Science ®Google Scholar
• Zhou Y, Gammeltoft KA, Ryberg LA, et al. Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system. Sci Adv. 2022 Dec 21;8(51): eadd7197. Epub 2022 Dec 21. PMID: 36542720; PMCID: PMC9770952. doi: 10.1126/sciadv.add7197
   PubMed Web of Science ®Google Scholar
• 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 Jun;298(6):101972. Epub 2022 Apr 22. PMID: 35461811; PMCID: PMC9023115. doi: 10.1016/j.jbc.2022.101972
   PubMedGoogle Scholar
• Moghadasi SA, Heilmann E, Khalil A, et al. Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors. Sci Adv. 2023 Mar 29;9(13): eade8778. Epub 2023 Mar 29. PMID: 36989354; PMCID: PMC10058310. doi: 10.1126/sciadv.ade8778
   PubMed Web of Science ®Google Scholar
• 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 Feb 28;14(1):e0281522. Epub 2023 Jan 10. PMID: 36625640; PMCID: PMC9973015. doi: 10.1128/mbio.02815-22
   PubMed Web of Science ®Google Scholar
• Wagoner J, Herring S, Hsiang TY, et al. Combinations of host- and virus-targeting antiviral drugs confer synergistic Suppression of SARS-CoV-2. Microbiol Spectr. 2022 Oct 26;10(5): e0333122. Epub 2022 Oct 3. PMID: 36190406; PMCID: PMC9718484. doi: 10.1128/spectrum.03331-22
   PubMed Web of Science ®Google Scholar
• Kong K, Chang Y, Qiao H, et al. Paxlovid accelerates cartilage degeneration and senescence through activating endoplasmic reticulum stress and interfering redox homeostasis. J Transl Med. 2022;20(1):549. doi: 10.1186/s12967-022-03770-4
   PubMed Web of Science ®Google Scholar
• Leist SR, KH D 3rd, Schäfer A, et al. A mouse-Adapted SARS-CoV-2 Induces acute lung injury and mortality in standard Laboratory mice. Cell. 2020 Nov 12;183(4): 1070–1085.e12. Epub 2020 Sep 23. PMID: 33031744; PMCID: PMC7510428. doi: 10.1016/j.cell.2020.09.050
   PubMed Web of Science ®Google Scholar
• Jeong JH, Chokkakula S, Min SC, et al. Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice. Antiviral Res. 2022 Dec;208:105430. Epub 2022 Oct 6. PMID: 36209984; PMCID: PMC9535923. doi: 10.1016/j.antiviral.2022.105430
   PubMed Web of Science ®Google Scholar
• Abdelnabi R, Foo CS, Jochmans D, et al. The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern. Nat Commun. 2022 Feb 15;13(1):719. PMID: 35169114; PMCID: PMC8847371. doi: 10.1038/s41467-022-28354-0
   PubMed Web of Science ®Google Scholar
• Rosenke K, Lewis MC, Feldmann F, et al. Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques. JCI Insight. 2023 Feb 22;8(4):e166485. PMID: 36574296; PMCID: PMC9977490. doi: 10.1172/jci.insight.166485
   PubMed Web of Science ®Google Scholar
• Catlin NR, Bowman CJ, Campion SN, et al. Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models. Reprod Toxicol. 2022 Mar; 108:56–61. doi: 10.1016/j.reprotox.2022.01.006. Epub 2022 Jan 31. PMID: 35101563; PMCID: PMC8801796.
   PubMed Web of Science ®Google Scholar
• Lea AP, Faulds D. Ritonavir. Drugs. 1996 Oct;52(4):541–546. doi: 10.2165/00003495
   PubMed Web of Science ®Google Scholar
• Pinzi L, Rastelli G. Molecular docking: Shifting Paradigms in drug discovery. Int J Mol Sci. 2019;20:4331.
   PubMed Web of Science ®Google Scholar
• Zhu J, Zhang H, Lin Q, et al. Progress on SARS-CoV-2 3CLpro inhibitors: Inspiration from SARS-CoV 3CLpro Peptidomimetics and small-molecule anti-Inflammatory compounds. Drug Des Devel Ther. 2022;16:1067–1082. doi: 10.2147/DDDT.S359009
   PubMed Web of Science ®Google Scholar
• Gonzalez Lomeli F, Elmaraghy N, Castro A, et al. Conserved targets to Prevent emerging coronaviruses. Viruses. 2022;14(3):563. doi: 10.3390/v14030563
   PubMed Web of Science ®Google Scholar
• Ahmad B, Batool M, Ain Qu A, et al. Exploration of the binding mechanism of the SARS-CoV-2 protease inhibitor PF-07321332 through molecular dynamics and binding free energy simulations. Int J Mol Sci. 2021;22:9124. doi: 10.3390/ijms22179124
   PubMed Web of Science ®Google Scholar
• Liu Y, Ma R, Fan H, et al. Pharmacophore Oriented MP2 Characterization of Charge Distribution for anti-SARS-CoV-2 inhibitor nirmatrelvir. J Mol Struct. 2023;1290:135871.
   PubMed Web of Science ®Google Scholar
• Li J, Wang Y, Solanki K, et al. Nirmatrelvir exerts distinct antiviral potency against several human coronaviruses. Antiviral Res. 2023;211:105555.
   PubMed Web of Science ®Google Scholar
• Singh RSP, Toussi SS, Hackman F, et al. Innovative randomized phase I study and dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 trial of nirmatrelvir. Clin Pharmacol Ther. 2022 Jul;112(1):101–111. Epub 2022 May 4. PMID: 35388471; PMCID: PMC9087011. doi: 10.1002/cpt.2603
   PubMedGoogle Scholar
• Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, Nonhospitalized adults with covid-19. N Engl J Med. 2022 Apr 14;386(15):1397–1408. Epub 2022 Feb 16. PMID: 35172054; PMCID: PMC8908851. doi: 10.1056/NEJMoa2118542
   PubMed Web of Science ®Google Scholar
• Pfizer’s novel COVID-19 oral antiviral treatment candidate reduced risk of hospitalization or death by 89% in Interim analysis of phase 2/3 EPIC-HR study. Accessed online at https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate
   Google Scholar
• Pfizer initiates phase 2/3 study of novel COVID-19 oral treatment in Pediatric Participants. Accessed online at https://www.pfizer.com/news/press-release/press-release-detail/pfizer-initiates-phase-23-study-novel-covid-19-oral.
   Google Scholar
• Bose-Brill S, Hirabayashi K, Pajor NM, et al. Pediatric nirmatrelvir/ritonavir Prescribing Patterns during the COVID-19 pandemic. medRxiv [Preprint]. 2022 Dec 26; 2022.12.23.22283868 PMID: 36597537; PMCID: PMC9810217. doi: 10.1101/2022.12.23.22283868
   Google Scholar
• Wang L, Berger NA, Davis PB, et al. COVID-19 rebound after Paxlovid and molnupiravir during January-June 2022. medRxiv [Preprint]. 2022 Jun 22. 2022.06.21.22276724 PMID: 35794889; PMCID: PMC9258292. doi: 10.1101/2022.06.21.22276724
   Google Scholar
• Wang L, Volkow ND, Davis PB, et al. COVID-19 rebound after Paxlovid treatment during Omicron BA.5 vs BA.2.12.1 subvariant predominance period. medRxiv [Preprint]. 2022 Aug 6. 2022.08.04.22278450 PMID: 35982673; PMCID: PMC9387159. doi: 10.1101/2022.08.04.22278450
   Google Scholar
• Wong GL, Yip TC, Lai MS, et al. Incidence of viral rebound after treatment with nirmatrelvir-ritonavir and molnupiravir. JAMA Netw Open. 2022;5(12):e2245086. doi: 10.1001/jamanetworkopen.2022.45086
   PubMed Web of Science ®Google Scholar
• Alshanqeeti S, Bhargava A. COVID-19 rebound after Paxlovid treatment: A case series and review of Literature. Cureus. 2022 Jun 23;14(6):e26239. PMID: 35898366; PMCID: PMC9308388. doi: 10.7759/cureus.26239
   PubMed Web of Science ®Google Scholar
• Boucau J, Uddin R, Marino C, et al. Characterization of Virologic rebound Following nirmatrelvir-ritonavir treatment for coronavirus disease 2019 (COVID-19). Clin Infect Dis. 2023 Feb 8;76(3): e526–e529. PMID: 35737946; PMCID: PMC9384370. doi: 10.1093/cid/ciac512
   PubMed Web of Science ®Google Scholar
• Malden DE, Hong V, Lewin BJ, et al. Hospitalization and Emergency department Encounters for COVID-19 after Paxlovid treatment - California, December 2021-May 2022. MMWR Morb Mortal Wkly Rep. 2022 Jun 24;71(25):830–833. PMID: 35737591. doi: 10.15585/mmwr.mm7125e2
   PubMed Web of Science ®Google Scholar
• Patel R, Kaki M, Potluri VS, et al. A comprehensive review of SARS-CoV-2 vaccines: pfizer, Moderna & Johnson & Johnson. Hum Vaccin Immunother. 2022;18(1):2002083. PMID: 35130825; PMCID: PMC8862159. doi: 10.1080/21645515.2021.2002083
   PubMed Web of Science ®Google Scholar
• Rosario García-Lozano M D, Dragoni F, Gallego P, et al. Piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. In vitro antiviral activity evaluation against Zika and Dengue viruses. Bioorg Chem [ PMID: 36801791]. 2023;133:106408. doi: 10.1016/j.bioorg.2023.106408
   PubMed Web of Science ®Google Scholar