In the age of Omicron variant: Paxlovid raises new hopes of COVID‐19 recovery
2021; Wiley; Volume: 94; Issue: 5 Linguagem: Inglês
10.1002/jmv.27540
ISSN1096-9071
Autores Tópico(s)vaccines and immunoinformatics approaches
ResumoSince the outbreak of COVID-19, caused by the SARS-CoV-2, in December 2019, the ongoing pandemic has posed 5 318 216 deaths worldwide.1 Vaccines, traditional Chinese medicine, and small-molecule antiviral therapies were considered the emergency responders on the COVID-19.2 However, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) variants of SARS-CoV-2 cause the resurge of infections. More worrisome, the novel Omicron (B.1.1.529) variant, firstly identified in South Africa on November 24, 2021, has put the whole world on red alert.3 Based on the unprecedented number of mutations (>32 mutations in Spike), and enhanced transmissibility (three times more infectious or severe than the original Wuhan strain), on November 26, 2021, the World Health Organization announced it to be a variant of concern.4 Therefore, some necessary measures, such as wearing masks, getting vaccine booster doses, restricting gatherings, travel restrictions, increasing vaccination coverage (e.g., >80% of people in Africa have not had a single dose5), and gene sequencing could help to reduce the Omicron variant spread globally. As it stands, early data hint that the Omicron variant might alter responses to COVID-19 vaccines and weaken vaccine protection, as almost all vaccines targeted at the S protein.6 As for small molecule drugs, only an intravenous nucleotide prodrug remdesivir (Veklury®) was currently approved by the U.S. FDA for the treatment of SARS-CoV-2 infection, but it is difficult to be widely used in hospitalized patients due to its limitations and controversial efficacy.7 Only very recently, the oral antiviral candidate Paxlovid™ (PF-07321332 + ritonavir), developed by Pfizer Inc., raises new hopes of COVID-19 recovery in the age of Omicron variant.8 PF-07321332, the second-generation orally bioavailable SARS-CoV-2 main protease (Mpro) inhibitor developed by Pfizer Inc., is a novel molecular entity that combines the merits of both PF-07304814 and boceprevir.9-13 PF-07321332, recognized as a promising broad-spectrum agent, can be used to treat infections with multiple human coronaviruses in vitro, including SARS-CoV, SARS-CoV-2, HCoV-HKU1, HCoV-OC43, MERS-CoV, HCoV-229E, and HCoV-NL63.8 Owen et al. revealed that PF-07321332 exhibits strong anti-SARS-CoV-2 Mpro activity in Vero E6 cells with a half maximal effective concentration value of 74.5 nM without significant cytotoxicity.8 In addition, Owen et al. revealed that PF-07321332 can enhance anti-SARS-CoV-2 activity in a mouse-adapted SARS-CoV-2 MA10 model, resulting in significantly reduced multifocal pulmonary lesions and viral load in mouse lungs in a dose-dependent manner.8 PF-07321332 was found to be safe and well-tolerated with no adverse at oral dosing of 600 mg/kg/day in monkeys and 1000 mg/kg/day in rats for 14 days.8 PF-07321332 exhibits favorable oral bioavailability and promising pharmacokinetic properties in preclinical absorption, distribution, metabolism, and excretion studies, supporting progression into clinical studies. To elucidate the inhibitory mechanism at a molecular level, Rao et al. determined the 1.6-Å crystal structure of PF-07321332 in complex with SARS-CoV-2 Mpro (PDB: 7VH8), which indicates that PF-07321332 binds to the enzyme via the covalent linkage of Cys145 with nitrile carbon to form a reversible thioimidate adduct.14 Specifically, Nitsche's in vitro data suggest that Mpro mutants of SARS-CoV-2 variants remain susceptible to PF-07321332.15 They expressed five prevalent Mpro variants (including G15S, T21I, L89F, K90R, and L205V) in different SARS-CoV-2 lineages, and enzyme kinetics showed that PF-07321332 has promising potency against all the above-mentioned Mpro variants, implying that PF-07321332 could be effective in the management of the Omicron variant of SARS-CoV-2.15 In the Omicron variant, the P132H mutant was detected in the nsp5 (Mpro), but structural analysis demonstrated that this mutant was kept away from the active site and may not hinder the performance of anti-SARS-CoV-2 agents.16 Neyts et al. revealed that PF-07321332 (250 mg/kg, twice daily) can completely protect the Syrian golden hamsters against intranasal infection with Beta and Delta SARS-CoV-2 variants.17 To achieve a maximal anti-SARS-CoV-2 potency in clinical trials, PF-07321332 was combined with ritonavir, an HIV drug used to slow down the metabolism of PF-07321332 through inhibiting cytochrome P450 enzymes.18 For example, a double-blind, placebo-controlled phase II/III trial was conducted by Pfizer Inc. to evaluate the anti-SARS-CoV-2 efficacy of Paxlovid™ in 1219 nonhospitalized high-risk adult patients with COVID-19.19 The interim results showed that an 89% reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients administered within three days of symptom onset.19 Notably, Paxlovid™ does appear to be effective at preventing death in COVID-19 patients with high statistical significance (0/607 for Paxlovid™ group vs. 10/612 for the placebo group, p < 0.0001).19 This finding supports the potential value of Paxlovid™ as a promising therapy for COVID-19 patients. Moreover, three clinical trials (Clinical Trials Registration NCT04962022, NCT04962230, and NCT04756531) of Paxlovid™ have been completed, five clinical trials (NCT04960202, NCT05064800, NCT05005312, NCT05032950, and NCT05047601) of Paxlovid™ are currently underway and will be disclosed shortly. It is to be noted, however, that widespread use or misuse of Paxlovid™ may increase the number of Mpro mutations required for clinical resistance. Anyway, we sincerely hope that Pfizer's Paxlovid™ will prove to be a safe and effective therapy against SARS-CoV-2 in the age of Omicron variant. This study was supported by the project of the PhD research start-up fund of Qufu Normal University, China (Grant nos: 614901 and 615201). The authors declare that there are no conflict of interests. Zhonglei Wang: Conceptualization, writing—original draft, writing—review and editing, visualization, funding acquisition. Liyan Yang: Conceptualization, writing—review and editing, funding acquisition.
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