Naphthalen-1-ylethanamine-containing small molecule inhibitors of the papain-like protease of SARS-CoV-2

Kouki Shinohara; Takuya Kobayakawa; Kohei Tsuji; Yuki Takamatsu; Hiroaki Mitsuya; Hirokazu Tamamura

doi:10.1016/j.ejmech.2024.116963

Naphthalen-1-ylethanamine-containing small molecule inhibitors of the papain-like protease of SARS-CoV-2

Eur J Med Chem. 2024 Dec 15:280:116963. doi: 10.1016/j.ejmech.2024.116963. Epub 2024 Oct 18.

Authors

Kouki Shinohara¹, Takuya Kobayakawa¹, Kohei Tsuji¹, Yuki Takamatsu², Hiroaki Mitsuya³, Hirokazu Tamamura⁴

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 Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo, 162-8655, Japan.
³ Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo, 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States; Department of Clinical Sciences, Kumamoto University Hospital, Chuo-ku, Kumamoto, 860-8556, Japan.
⁴ Department of Medicinal Chemistry, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Chiyoda-ku, Tokyo, 101-0062, Japan. Electronic address: [email protected].

PMID: 39442336
DOI: 10.1016/j.ejmech.2024.116963

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M^pro) and a papain-like protease (PL^pro), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL^pro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL^pro showed that GRL-0048 noncovalently interacts with PL^pro, and there is a newly identified binding pocket in PL^pro. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds 1, 2b, and 3h, that have more potent inhibitory activity than GRL-0048.

Keywords: Coronavirus disease 2019 (COVID-19); Docking simulation; Papain-like protease inhibitor; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

MeSH terms

Antiviral Agents* / chemical synthesis
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
COVID-19 Drug Treatment
Coronavirus 3C Proteases / antagonists & inhibitors
Coronavirus 3C Proteases / metabolism
Coronavirus Papain-Like Proteases* / antagonists & inhibitors
Coronavirus Papain-Like Proteases* / chemistry
Coronavirus Papain-Like Proteases* / metabolism
Ethylamines / chemical synthesis
Ethylamines / chemistry
Ethylamines / pharmacology
Humans
Molecular Docking Simulation*
Molecular Structure
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
Structure-Activity Relationship

Substances

Antiviral Agents
Coronavirus 3C Proteases
Coronavirus Papain-Like Proteases
Naphthalenes
papain-like protease, SARS-CoV-2
Protease Inhibitors
Small Molecule Libraries
Ethylamines