27º SEMINARIO QUÍMICA ORGÁNICA IQUIR 2025

SEMINARIO QUÍMICA ORGÁNICA 17-11-25

EXPOSITOR: Dra. Nadia L. Martiren

TÍTULO: "Discovery of the Clinical Candidate S‑892216: A Second-Generation of SARS-CoV‑2 3CL Protease Inhibitor for Treating COVID-19".

FUENTE: Yuto Unoh,* Keiichiro Hirai, Shota Uehara, Sho Kawashima, Haruaki Nobori, Jun Sato, Hiromitsu Shibayama, Akihiro Hori, Kenji Nakahara, Kana Kurahashi, Masayuki Takamatsu, Shiho Yamamoto, Qianhui Zhang, Miki Tanimura, Reiko Dodo, Yuki Maruyama, Hirofumi Sawa, Ryosuke Watari, Tetsuya Miyano, Teruhisa Kato, Takafumi Sato, and Yuki Tachibana "Discovery of the Clinical Candidate S‑892216: A Second-Generation of SARS-CoV‑2 3CL Protease Inhibitor for Treating COVID-19" J. Med. Chem. 2025, 68, 21099−21119. DOI: https://doi.org/10.1021/acs.jmedchem.5c00754

DÍA, HORA y LUGAR: Lunes 17 de noviembre de 2025, 14:00 h, Aula 18 y virtual.

Modalidad virtual, Link: meet.google.com/hjn-ygro-twf (Plataforma MEET GOOGLE)

Resumen: 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 S-892216, a second-generation SARS-CoV-2 3C-like protease (3CLpro) inhibitor, to treat COVID-19. S-892216 is a reversible covalent 3CLpro inhibitor with highly potent antiviral activity and an EC50 value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound 1 revealed that introducing a nitrile warhead increased 3CLpro inhibition activity by 180-fold. Subsequent optimization efforts yielded S-892216, which combined a favorable pharmacokinetic profile and high off-target selectivity. S-892216 exhibited antiviral activity against diverse SARS-CoV-2 variants, including major mutations reducing antiviral ctivities of nirmatrelvir and ensitrelvir. In SARS-CoV-2-infected mice, S-892216 inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.