2. Academic Validation
  3. SARS-CoV‑2 Papain-Like Protease Inhibitors Based on Naphthalen-1-ylethanamine and Halogenated Benzene Moieties

SARS-CoV‑2 Papain-Like Protease Inhibitors Based on Naphthalen-1-ylethanamine and Halogenated Benzene Moieties

  • ACS Omega. 2025 Oct 2;10(40):47165-47175. doi: 10.1021/acsomega.5c05856.
Kouki Shinohara 1,  Takuya Kobayakawa 1,  Kohei Tsuji 1,  Yuki Takamatsu 2,  Hiroaki Mitsuya 2 3 4,  Hirokazu Tamamura 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Chiyoda-ku, Tokyo 101-0062, Japan.
  • 2 Department of Refractory Viral Infections, National Institute of Global Health and Medicine, Japan Institute for Health Security, Shinjuku-ku, Tokyo 162-8655, Japan.
  • 3 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 4 Department of Clinical Sciences, Kumamoto University Hospital, Chuo-ku, Kumamoto 860-8556, Japan.
PMID: 41114162 DOI: 10.1021/acsomega.5c05856
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative virus of COVID-19, remains a worldwide health threat. SARS-CoV-2 possesses two types of proteases: a main protease (Mpro, 3C-like) and a papain-like protease (PLpro). These proteases cleave two translated nonstructural proteins, pp1a and pp1ab, into viral functional proteins. In the present study, we developed new inhibitors targeting the PLpro of SARS-CoV-2 based on GRL-0048 (2) as a lead compound. Structure-activity relationship (SAR) researches on GRL-0048 (2) led to the finding of compound 9r, which showed significantly enhanced inhibitory activity against PLpro. This enhancement was accomplished by the introduction of a halogenated aromatic carbonyl moiety into the parent structure of GRL-0048 (2).

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