9HFX

Crystal structure of SARS CoV-2 3CLpro (Mpro) with ALG-097558

This is a non-PDB format compatible entry.

Summary for 9HFX

• Entry DOI: 10.2210/pdb9hfx/pdb
• Related: 9HFY
• Descriptor: 3C-like proteinase nsp5, (1~{S},2~{S},3~{S},6~{R},7~{R})-~{N}-[(2~{S})-1-azanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]-4-[(2~{S})-2-[[2-chloranyl-2,2-bis(fluoranyl)ethanoyl]amino]-3,3-dimethyl-butanoyl]-4-azatricyclo[5.2.1.0^{2,6}]decane-3-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: sars cov-2 3clpro, mpro, hydrolase, pan-coronavirus 3clpro inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34429.63

Authors

Tauchert, M.J.,Maskos, K.,McGowan, D.C.,Stoycheva, A.D. (deposition date: 2024-11-18, release date: 2025-07-16, Last modification date: 2025-07-23)

Primary citation

Bardiot, D.,McGowan, D.C.,Gupta, K.,Deval, J.,Chang, S.,Jekle, A.,Liu, C.,Stevens, S.,Serebryany, V.,Tauchert, M.J.,Maskos, K.,Stoycheva, A.D.,Ren, S.,Jaisinghani, R.,Faucher, M.O.,Lin, T.I.,Boland, S.,Chaltin, P.,Marchand, A.,Wuyts, J.,De Jonghe, S.,Jochmans, D.,Anugu, S.,Baloju, V.,Deta, K.,Welch, M.,Leyssen, P.,Neyts, J.,Laporte, M.,Abdelnabi, R.,Hu, H.,Zhang, P.,Le, K.,Chanda, S.,Smith, D.B.,Raboisson, P.,Beigelman, L.,Symons, J.A.,Blatt, L.,Vandyck, K.
Discovery and Preclinical Profile of ALG-097558, a Pan-Coronavirus 3CLpro Inhibitor.
J.Med.Chem., 68:13436-13454, 2025

PubMed Abstract: The SARS-CoV-2 outbreak of 2019 had a devastating impact on global health and economies worldwide. The viral cysteine protease (3CLpro) is responsible for viral polypeptide bond cleavages and is therefore an essential target to inhibit viral replication. Here, we report the discovery of an orally available, reversible covalent inhibitor of the SARS-CoV-2 main protease that is also highly active across other human coronaviruses and demonstrated oral efficacy in a Syrian hamster infection model at low plasma concentrations. Projection of pharmacokinetics (PK) in humans, based on PK studies in preclinical species and enhanced in vitro/in vivo efficacy of ALG-097558 () indicated the potential for BID dosing without the need for ritonavir, the PK boosting component of Paxlovid. After preclinical safety and pharmacological studies, ALG-097558 has progressed to phase 1 clinical trials.

PubMed: 40586480
DOI: 10.1021/acs.jmedchem.5c00088

Experimental method

X-RAY DIFFRACTION (1.96 Å)