7AEH

SARS-CoV-2 main protease in a covalent complex with a pyridine derivative of ABT-957, compound 1

Summary for 7AEH

• Entry DOI: 10.2210/pdb7aeh/pdb
• Descriptor: 3C-like proteinase nsp5, DIMETHYL SULFOXIDE, (2~{R})-5-oxidanylidene-~{N}-[(2~{R},3~{S})-3-oxidanyl-4-oxidanylidene-1-phenyl-4-(pyridin-2-ylmethylamino)butan-2-yl]-1-(phenylmethyl)pyrrolidine-2-carboxamide, ... (4 entities in total)
• Functional Keywords: covid-19, inhibitor, protease, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34496.51

Authors

Owen, C.D.,Redhead, M.A.,Lukacik, P.,Strain-Damerell, C.,Fearon, D.,Brewitz, L.,Collette, A.,Robinson, C.,Collins, P.,Radoux, C.,Navratilova, I.,Douangamath, A.,von Delft, F.,Malla, T.R.,Nugen, T.,Hull, H.,Tumber, A.,Schofield, C.J.,Hallet, D.,Stuart, D.I.,Hopkins, A.L.,Walsh, M.A. (deposition date: 2020-09-17, release date: 2021-07-07, Last modification date: 2024-11-06)

Primary citation

Redhead, M.A.,Owen, C.D.,Brewitz, L.,Collette, A.H.,Lukacik, P.,Strain-Damerell, C.,Robinson, S.W.,Collins, P.M.,Schafer, P.,Swindells, M.,Radoux, C.J.,Hopkins, I.N.,Fearon, D.,Douangamath, A.,von Delft, F.,Malla, T.R.,Vangeel, L.,Vercruysse, T.,Thibaut, J.,Leyssen, P.,Nguyen, T.T.,Hull, M.,Tumber, A.,Hallett, D.J.,Schofield, C.J.,Stuart, D.I.,Hopkins, A.L.,Walsh, M.A.
Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19.
Sci Rep, 11:13208-13208, 2021

PubMed Abstract: Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (M) and the papain-like protease (PL) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target M and PL, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of M (IC 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PL (IC 300 nM, K 200 nM) and is the first reported PL inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.

PubMed: 34168183
DOI: 10.1038/s41598-021-92416-4

Experimental method

X-RAY DIFFRACTION (1.3 Å)