7RFR

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

Summary for 7RFR

• Entry DOI: 10.2210/pdb7rfr/pdb
• Descriptor: 3C-like proteinase, (1R,2S,5S)-N-{(1S,2S)-1-(1,3-benzothiazol-2-yl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-(4-methoxy-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: protease sars-cov-2 covalent complex inhibitor, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 68854.53

Authors

Gajiwala, K.S.,Ferre, R.A.,Liu, W.,Stewart, A.E. (deposition date: 2021-07-14, release date: 2021-11-10, Last modification date: 2023-10-18)

Primary citation

Owen, D.R.,Allerton, C.M.N.,Anderson, A.S.,Aschenbrenner, L.,Avery, M.,Berritt, S.,Boras, B.,Cardin, R.D.,Carlo, A.,Coffman, K.J.,Dantonio, A.,Di, L.,Eng, H.,Ferre, R.,Gajiwala, K.S.,Gibson, S.A.,Greasley, S.E.,Hurst, B.L.,Kadar, E.P.,Kalgutkar, A.S.,Lee, J.C.,Lee, J.,Liu, W.,Mason, S.W.,Noell, S.,Novak, J.J.,Obach, R.S.,Ogilvie, K.,Patel, N.C.,Pettersson, M.,Rai, D.K.,Reese, M.R.,Sammons, M.F.,Sathish, J.G.,Singh, R.S.P.,Steppan, C.M.,Stewart, A.E.,Tuttle, J.B.,Updyke, L.,Verhoest, P.R.,Wei, L.,Yang, Q.,Zhu, Y.
An oral SARS-CoV-2 M pro inhibitor clinical candidate for the treatment of COVID-19.
Science, 374:1586-1593, 2021

PubMed 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.

PubMed: 34726479
DOI: 10.1126/science.abl4784

Experimental method

X-RAY DIFFRACTION (1.626 Å)