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

Introduction: Nirmatrelvir/ritonavir (Paxlovid) represent an oral antiviral therapy approved for the treatment of COVID-19. Extensive and studies have reported the promising activity of nirmatrelvir/ritonavir against numerous emerging viruses. This combination consists of nirmatrelvir, a protease reversible inhibitor of coronavirus 3CL mainly metabolized by cytochrome P450 (CYP)3A4, and ritonavir, an inhibitor of the CYP3A isoforms that enhances the efficacy of nirmatrelvir by fixing its suboptimal pharmacokinetic properties.