8V4U

Structure of SARS-CoV-2 main protease in complex with a covalent inhibitor

Summary for 8V4U

• Entry DOI: 10.2210/pdb8v4u/pdb
• Descriptor: 3C-like proteinase nsp5, N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1Z,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-(trifluoromethyl)-L-prolinamide (3 entities in total)
• Functional Keywords: protease sars-cov-2 covalent complex inhibitor, hydrolase-inhibitor complex, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68634.10

Authors

Greasley, S.E.,Ferre, R.A.,Liu, W. (deposition date: 2023-11-29, release date: 2024-05-15, Last modification date: 2024-10-23)

Primary citation

Allerton, C.M.N.,Arcari, J.T.,Aschenbrenner, L.M.,Avery, M.,Bechle, B.M.,Behzadi, M.A.,Boras, B.,Buzon, L.M.,Cardin, R.D.,Catlin, N.R.,Carlo, A.A.,Coffman, K.J.,Dantonio, A.,Di, L.,Eng, H.,Farley, K.A.,Ferre, R.A.,Gernhardt, S.S.,Gibson, S.A.,Greasley, S.E.,Greenfield, S.R.,Hurst, B.L.,Kalgutkar, A.S.,Kimoto, E.,Lanyon, L.F.,Lovett, G.H.,Lian, Y.,Liu, W.,Martinez Alsina, L.A.,Noell, S.,Obach, R.S.,Owen, D.R.,Patel, N.C.,Rai, D.K.,Reese, M.R.,Rothan, H.A.,Sakata, S.,Sammons, M.F.,Sathish, J.G.,Sharma, R.,Steppan, C.M.,Tuttle, J.B.,Verhoest, P.R.,Wei, L.,Yang, Q.,Yurgelonis, I.,Zhu, Y.
A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.
J.Med.Chem., 67:13550-13571, 2024

PubMed Abstract: Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.

PubMed: 38687966
DOI: 10.1021/acs.jmedchem.3c02469

Experimental method

X-RAY DIFFRACTION (1.819 Å)