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

Production of a versatile SARS‐CoV‐2 main protease biosensor based on a dimerization‐dependent red fluorescent protein

“…because of the distinct catalytic features of ddRFP biosensor. 4,7 These results demonstrate the feasibility and reliability of ddRFP biosensor for the evaluation of Mpro inhibitors by monitoring the change of RFU value.…”

SARS‐CoV‐2 main protease inhibitors: What is moving in the field of peptides and peptidomimetics?

“…On the other hand, at the C-terminal position, nirmalterlvir has a pyrrolidone-containing Gln mimetic at P1, which bear a nitrile warhead that forms a reversible covalent adduct with Cys145 of SARS-CoV-2 Mpro at the catalytic site (Ki = 3.11 nM) [27] . Nirmatrelvir displays also inhibiting activity on other human coronaviruses in vitro, and has excellent activity and safety profile in vivo, with remarkable selectivity against human elastase, cathepsins and caspases [28,29] . This inhibitor was commercialized as Paxlovid, a mixture of nirmaltrevir (2) and ritonavir, a drug initially launched for the treatment of HIV-1 infection.…”

“… 27 Nirmatrelvir displays also inhibiting activity on other human coronaviruses in vitro and has excellent activity and safety profile in vivo, with remarkable selectivity against human elastase, cathepsins, and caspases. 28 , 29 This inhibitor was commercialized as Paxlovid, a mixture of nirmatrelvir ( 2 ) and ritonavir, a drug initially launched for the treatment of HIV‐1 infection. The role of ritonavir in this pharmaceutical preparation is to preserve nirmatrelvir from easy metabolic degradation, because ritonavir acts as a good inhibitor of liver CYP3A4 cytocrome.…”

Recent updates on the biological efficacy of approved drugs and potent synthetic compounds against SARS-CoV-2

“…Currently, a newly synthesized compound known as Nirmatrelvir (PF-07321332) targeting 3CLpro developed by Pfizer has got approval for its emergency use, and results have shown that the use of Nirmatrelvir in combination with ritonavir, reduced the number of COVID-19 related hospitalizations. 23 We have reviewed the antiviral data of the synthetic compounds developed exclusively for SARS-CoV-2 along with the biological efficacy of the medications that have been modified and approved for treating other diseases. The main focus among synthesized compounds was on peptide inhibitors as one of them (Nirmatrelvir) was recently approved for it's use against SARS-CoV-2.…”