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Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease.
Hirose, Yuya; Shindo, Naoya; Mori, Makiko; Onitsuka, Satsuki; Isogai, Hikaru; Hamada, Rui; Hiramoto, Tadanari; Ochi, Jinta; Takahashi, Daisuke; Ueda, Tadashi; Caaveiro, Jose M M; Yoshida, Yuya; Ohdo, Shigehiro; Matsunaga, Naoya; Toba, Shinsuke; Sasaki, Michihito; Orba, Yasuko; Sawa, Hirofumi; Sato, Akihiko; Kawanishi, Eiji; Ojida, Akio.
  • Hirose Y; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Shindo N; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Mori M; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Onitsuka S; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Isogai H; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Hamada R; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Hiramoto T; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Ochi J; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Takahashi D; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Ueda T; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Caaveiro JMM; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Yoshida Y; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Ohdo S; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Matsunaga N; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • Toba S; International Institute for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo001-0020, Japan.
  • Sasaki M; Drug Discovery and Disease Research Laboratory, Shionogi & Co. Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka561-0825, Japan.
  • Orba Y; International Institute for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo001-0020, Japan.
  • Sawa H; International Institute for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo001-0020, Japan.
  • Sato A; International Institute for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo001-0020, Japan.
  • Kawanishi E; One Health Research Center, Hokkaido University, North 18, West 9 Kita-ku, Sapporo060-0818, Japan.
  • Ojida A; Global Virus Network, 725 West Lombard St. Room S413, Baltimore, Maryland21201, United States.
J Med Chem ; 65(20): 13852-13865, 2022 10 27.
Article in English | MEDLINE | ID: covidwho-2062145
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 3C-like protease (3CLpro) is a promising target for COVID-19 treatment. Here, we report a new class of covalent inhibitors of 3CLpro that possess chlorofluoroacetamide (CFA) as a cysteine-reactive warhead. Based on an aza-peptide scaffold, we synthesized a series of CFA derivatives in enantiopure form and evaluated their biochemical efficiency. The data revealed that 8a (YH-6) with the R configuration at the CFA unit strongly blocks SARS-CoV-2 replication in infected cells, and its potency is comparable to that of nirmatrelvir. X-ray structural analysis showed that YH-6 formed a covalent bond with Cys145 at the catalytic center of 3CLpro. The strong antiviral activity and favorable pharmacokinetic properties of YH-6 suggest its potential as a lead compound for the treatment of COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.2c01081

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.2c01081