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

Abstract

The rapid development of effective vaccines to combat the SARS-CoV-2 virus has been an effective counter measure to decrease hospitalization and the mortality rate in many countries. However, with the risk of mutated strains decreasing the efficacy of the vaccine, there has been an increasing demand for antivirals to treat COVID-19. While antivirals, such as remdesivir, have had some success treating COVID-19 patients in hospital settings, there is a need for orally bioavailable, cost-effective antivirals that can be administered in outpatient settings to minimize COVID-19-related hospitalizations and death. Nirmatrelvir (PF-07321332) is an orally bioavailable M^pro (also called 3CL^pro) inhibitor developed by Pfizer. It is administered in combination with ritonavir, a potent CYP3A4 inhibitor that decreases the metabolism of nirmatrelvir. This review seeks to outline the history of the rational design, the target selectivity, synthesis, drug resistance, and future perspectives of nirmatrelvir. Graphical abstract.

Keywords: Antiviral; Main protease; Nirmatrelvir; Paxlovid; SARS-CoV-2.

Graphical abstract

Fig. 1

Rational design of nirmatrelvir. A Chemical structures of remdesivir (1), molnupiravir (2), nirmatrelvir (3), ritonavir (4), PF-00835231 (5), PF-07304814 (6), GC-376 (7), rupintrivir (8), boceprevir (9), vidagliptin (10), odanacatib (11), IcatCXPZ-0 (12), compound 13, and Cbz-AVLQ-CN (14). The nirmatrelvir substitutions, P, are labeled by color: the P1 group is shown in red, P1’ in orange, P2 in pink, P3 in green, and P4 in blue; similar moieties present on nirmatrelvir (3) are colored on other molecules. B The cyclization between the glutamine sidechain amide with the warhead carbonyl [24]

Scheme 1

A A synthetic method for the synthesis of nirmatrelvir (3) developed by Pfizer. Two steps are utilized to generate the intermediate (20) with a 96% yield. The six-step synthesis has a total yield of 49.6% to synthesize the nirmatrelvir, MTBE solvate, and recrystallization is conducted to purify the solvate [16]. B The synthetic method for the synthesis of nirmatrelvir (3) was reported by Zhau et al. The two-step synthesis has a total yield of 60% [37]

Fig. 2

Chemical structure of the nirmatrelvir (3) and the thioimidate complex formed after reversable covalent inhibition with the M^pro catalytic cysteine [42]

Fig. 3

A The zoom-in view of the substrate-binding pocket. B Diagram of the interactions between nirmatrelvir (3) and SARS-CoV-2 M^pro generated in MOE [41]

Fig. 4

Metabolism of nirmatrelvir (3) via liver microsomes and hepatocytes from rat, monkey, and human

Fig. 5

SARS-CoV-2 M^pro mutants. High frequency M^pro mutants are mapped to the X-ray crystal structure of SARS-CoV-2 M^pro in complex with nirmatrelvir (PDB: 7SI9). Nirmatrelvir (3) is shown in sticks and colored in yellow. The catalytic C145 is shown in spheres and colored in magenta. The high frequency mutant residues G15S, T21I, L89F, K90R, P132H, L205V, and A260V are shown in spheres and colored in marine