Tweet
Eur J Med Chem
. 2024 Oct 18:280:116963.
doi: 10.1016/j.ejmech.2024.116963. Online ahead of print. Naphthalen-1-ylethanamine-containing small molecule inhibitors of the papain-like protease of SARS-CoV-2
Kouki Shinohara 1 , Takuya Kobayakawa 1 , Kohei Tsuji 1 , Yuki Takamatsu 2 , Hiroaki Mitsuya 3 , Hirokazu Tamamura 4
Affiliations
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 (Mpro) and a papain-like protease (PLpro), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PLpro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PLpro showed that GRL-0048 noncovalently interacts with PLpro, and there is a newly identified binding pocket in PLpro. 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).
. 2024 Oct 18:280:116963.
doi: 10.1016/j.ejmech.2024.116963. Online ahead of print. Naphthalen-1-ylethanamine-containing small molecule inhibitors of the papain-like protease of SARS-CoV-2
Kouki Shinohara 1 , Takuya Kobayakawa 1 , Kohei Tsuji 1 , Yuki Takamatsu 2 , Hiroaki Mitsuya 3 , Hirokazu Tamamura 4
Affiliations
- PMID: 39442336
- DOI: 10.1016/j.ejmech.2024.116963
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 (Mpro) and a papain-like protease (PLpro), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PLpro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PLpro showed that GRL-0048 noncovalently interacts with PLpro, and there is a newly identified binding pocket in PLpro. 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).