Nirmatrelvir is an oral protease inhibitor with emergency use authorization for the treatment of mild-to-moderate COVID-19. In December 2021 Paxlovid, a co-package of nirmatrelvir and ritonavir, was granted emergency use by the FDA. Paxlovid was approved for use in Canada in January 2022 for the treatment of adult patients with mild-moderate COVID-19. Later, it was granted conditional marketing authorization by the European Commission on January 27, 2022. Severe acute respiratory syndrome conronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, and is a respiratory disease that is capable of progressing to viral pneumonia and acute respiratory distress syndrome (ARDS). COVID-19 can be fatal. Like other RNA viruses, SARS-CoV-2 depends on RNA-dependent RNA polymerase (RdRp) for genomic replication. SARS-CoV-2 lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. Viral RNA is released from the mature SARS-CoV-2 virion and translated at the endoplasmic reticulum. SARS-CoV-2 RNA is translated into Replicase polypotein 1ab by host ribosomes. Replicase Protein 1ab is regularly cleaved by SARS-CoV-2 3C-like proteinase nsp5 and Papain-like protease nsp3 into various proteins required for RNA replication, mature virus synthesis, and the enzymes required for the cleavage of the polyprotein. These proteins include host translation inhibitor nsp1, non-structural protein 2, papain-like protease nsp3, non-structural protein 4, 3C-like proteinase nsp5, non-structural protein 6, non-structural protein 7, non-structural protein 8, RNA-capping enzyme subunit nsp9, non-structural protein 10, RNA-directed RNA polymerase nsp12, helicase nsp13, guanine-N7 methyltransferase nsp14, uridylate-specific endoribonuclease nsp15, and 2'-O-methyltransferase nsp16. SARS-CoV-2 RNA that was released from the virus is normally replicated by RNA polymerase which is comprised of nsp7, nsp8, and nsp12. Nimatrelvir inhibits a cysteine residue in 3C-like protease (3-CL) of SARS-CoV-2, which is the main protease that cleaves replicase polyprotein 1ab. The cysteine is responsible for the activity of the 3CL. This prevents the polyprotein from being cleaved into the various nonstructural proteins required for viral RNA replication, including proteases. SARS-CoV-2 RNA that was released is prevented from replicating due to the inhibition of polyprotein cleavage. Due to the inhibition of RNA replication, mature, infective viruses are unable to be assembled and released.

Nirmatrelvir Pathway References