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COVID-19 경구용 치료제 Paxlovid

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2021-12-29 14:20
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최근 미국과 한국에서 긴급사용(Emergency Use Authorization)이 승인이 된 COVID-19 경구용 치료제인 화이자의 Paxlovid (Nirmatrelvir+ritonavir 혼합제)의 주성분인 Nirmatrelvir (개발코드: PF-07321332)에 대한 화이자 연구진의 논문입니다. Nirmatrelvir는 코로나바이러스의 복제에 핵심적인 역할을 하는 main protease (3CL protease) 저해제로서, main protease active site에 있는 thiol group (Cys-145) 과 반응하는 warhead 부분에 특이하게 nitrile (CN) group 이 도입된 tripeptide 화합물이다. Nirmatrelvir는 인체내서 쉽게 대사가 되므로 CYP3A4 억제제인 리토나비르(ritonavir)와 혼합제로 사용된다.

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“An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19”

Owen et al., Science 374, 1586–1593 (2021) 24 December 2021

<Abstract>

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.