PF-07321332 (Nirmatrelvir) is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro [1]. PF-07321332 inhibited activity against SARS-CoV-2 Mpro with the IC50 value of 0.023 µM [2].
PF-07321332 demonstrated potent inhibition in FRET Mpro assays representing Mpro from all coronavirus types known to infect humans [3,4,5], including beta-coronaviruses (SARS-CoV-2, SARS-CoV-1, HKU1, OC43, and MERS-CoV) as well as alpha-coronaviruses (229E and NL63) [6]. At the concentration tested (100 µM) of PF-07321332, no inhibitory effects were noted against several mammalian cysteine (caspase 2, cathepsin B, and cathepsin L), serine (chymotrypsin, elastase, and thrombin) and aspartyl (cathepsin D) proteases [6]. Treatment of dNHBE cells with varying concentrations of PF-07321332 for 3 days led to inhibition of SARS-CoV-2 viral replication, with EC50 and EC90 values of 61.8 and 181 nM, respectively [6].
After infection with SARS-CoV-2 MA10, mice treated twice daily with PF-07321332 (at both 300 and 1000 mg/kg doses) were protected from weight loss compared with vehicle-treated mice. At 4 days after infection, mice were sacrificed and lung viral titers were evaluated in CCID50 assays. Infected animals in the placebo group had robust infection in the lungs, whereas virus levels in mice treated with PF-07321332 were significantly reduced (300 and 1000 mg/kg PF-07321332-treated groups, respectively) [6]. PF-07321332 exhibited moderate plasma clearance (CLp) in rats and monkeys, with elimination half-lives (t1/2) of 5 hours and <1 hour, respectively, after intravenous dosing [6].
References:
[1]. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19[J]. New England Journal of Medicine, 2022, 386(15): 1397-1408.
[2]. Li J, Lin C, Zhou X, et al. Structural Basis of the Main Proteases of Coronavirus Bound to Drug Candidate PF-07321332[J]. Journal of Virology, 2022, 96(8): e02013-21.
[3]. Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China[J]. Nature, 2020, 579(7798): 265-269.
[4]. Zhou P, Yang X L, Wang X G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin[J]. nature, 2020, 579(7798): 270-273.
[5]. Cui J, Li F, Shi Z L. Origin and evolution of pathogenic coronaviruses[J]. Nature reviews microbiology, 2019, 17(3): 181-192.
[6]. Owen D R, Allerton C M N, Anderson A S, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19[J]. Science, 2021, 374(6575): 1586-1593.