An Oral SARS-CoV-2 M^pro Inhibitor Clinical Candidate for the Treatment of COVID-19

Abstract

The worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to counter 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 I clinical trial in healthy human participants. Clinical Trial Registration ID #: NCT04756531

Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules

“…Notably, none of them span the entire catalytic cavity, which is likely to explain their lower inhibition activity compared to latest peptidomimetic covalent inhibitors that entered clinical trials. 56 These results jointly corroborate the complexity of Mpro as a CADD target and once more highlighted the limited success of recent SBVS campaigns in general and docking studies in particular. 57 Nevertheless, the novel noncovalent Mpro inhibitors that we report here provide a significant number of starting points for their future optimization into drug candidates, following the path of recent successful stories in developing low nanomolar noncovalent Mpro inhibitors from high micromolar hits identified by docking and consensus filtering.…”

Design of SARS-CoV-2 Mpro, PLpro dual-target inhibitors based on deep reinforcement learning and virtual screening

“…The hydrogen bonding interaction of the ligand with Glu166 is important because Glu166 is responsible for the formation of SARS-CoV-2 homo-dimer and the interaction with Glu166 may lead to the formation of inactive monomer, which will affect the enzyme activity of Mpro [ 49 ]. All three compounds interacted with His41, Cys145 and Glu166, which are similar to PF-07321332 [ 50 ] and α-ketoamide that were previously reported to have inhibitory effects on Mpro. For PLpro, all three compounds form hydrogen bonding interactions with Cys111.…”

“…On the basis of the preceding analysis, all three compounds interact with amino acid residues in the catalytic dyad of Mpro (His41, Cys145) and the catalytic triad of PLpro (Cys111, His272, Asp286). The benzene or naphthalene ring of A3175, A3659 and A3777 occupy the pocket where His41 is located of Mpro, and all three interact with key amino acid residues such as Cys145 and Glu166 through the carbonyl group on the backbone [ 50 ]. Previous studies found that the BL2 loop (residues 265–271) of the PLpro protein had a role in substrate recognition.…”

Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules

“…We note that piraceram itself can also be readily oxidized to the N,O-acetal but the subsequent methylation proved to be low yielding (~30%). Finally, a complex fragment of PF-07321332, 27 a potential anti-viral compound developed by Pfizer currently in Phase I clinical trials to treat COVID-19, underwent methylation to generate compound 20 with excellent regio-and chemoselectivity without rupture of the cyclopropane ring. Again, this substrate is likely incompatible with existing methylation strategies that rely on radical C-H activation.…”