9LVV

Crystal structure of SARS-CoV-2 3CL protease in complex with compound 17 (S-892216)

This is a non-PDB format compatible entry.

Summary for 9LVV

• Entry DOI: 10.2210/pdb9lvv/pdb
• Related: 9LVR 9LVT
• Descriptor: 3C-like proteinase, 1-(2-azanylideneethyl)-6-[6,6-bis(fluoranyl)-2-azaspiro[3.3]heptan-2-yl]-5-(3-chloranyl-4-fluoranyl-phenyl)-3-(5-chloranylpyridin-3-yl)pyrimidine-2,4-dione (3 entities in total)
• Functional Keywords: 3cl protease, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34494.00

Authors

Unoh, Y.,Hirai, K.,Uehara, S.,Kawashima, S.,Nobori, H.,Sato, J.,Shibayama, H.,Hori, A.,Nakahara, K.,Kurahashi, K.,Takamatsu, M.,Yamamoto, S.,Zhang, O.,Tanimura, M.,Dodo, R.,Maruyama, Y.,Sawa, H.,Watari, R.,Miyano, T.,Kato, T.,Sato, T.,Tachibana, Y. (deposition date: 2025-02-12, release date: 2025-05-14, Last modification date: 2025-11-05)

Primary citation

Unoh, Y.,Hirai, K.,Uehara, S.,Kawashima, S.,Nobori, H.,Sato, J.,Shibayama, H.,Hori, A.,Nakahara, K.,Kurahashi, K.,Takamatsu, M.,Yamamoto, S.,Zhang, Q.,Tanimura, M.,Dodo, R.,Maruyama, Y.,Sawa, H.,Watari, R.,Miyano, T.,Kato, T.,Sato, T.,Tachibana, Y.
Discovery of the Clinical Candidate S-892216 : A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19.
J.Med.Chem., 68:21099-21119, 2025

PubMed Abstract: The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health and an unmet need for therapeutic options. Herein, we report the discovery of , a second-generation SARS-CoV-2 3C-like protease (3CL) inhibitor, to treat COVID-19. is a reversible covalent 3CL inhibitor with highly potent antiviral activity and an EC value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound revealed that introducing a nitrile warhead increased 3CL inhibition activity by 180-fold. Subsequent optimization efforts yielded , which combined a favorable pharmacokinetic profile and high off-target selectivity. exhibited antiviral activity against diverse SARS-CoV-2 variants, including major mutations reducing antiviral activities of nirmatrelvir and ensitrelvir. In SARS-CoV-2-infected mice, inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.

PubMed: 40616520
DOI: 10.1021/acs.jmedchem.5c00754

Experimental method

X-RAY DIFFRACTION (1.9 Å)