tetano
Editor, Senior Moderator
J Med Chem
. 2022 Oct 13.
doi: 10.1021/acs.jmedchem.2c01081. Online ahead of print.
Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease
Yuya Hirose[SUP] 1 [/SUP], Naoya Shindo[SUP] 1 [/SUP], Makiko Mori[SUP] 1 [/SUP], Satsuki Onitsuka[SUP] 1 [/SUP], Hikaru Isogai[SUP] 1 [/SUP], Rui Hamada[SUP] 1 [/SUP], Tadanari Hiramoto[SUP] 1 [/SUP], Jinta Ochi[SUP] 1 [/SUP], Daisuke Takahashi[SUP] 1 [/SUP], Tadashi Ueda[SUP] 1 [/SUP], Jose M M Caaveiro[SUP] 1 [/SUP], Yuya Yoshida[SUP] 1 [/SUP], Shigehiro Ohdo[SUP] 1 [/SUP], Naoya Matsunaga[SUP] 1 [/SUP], Shinsuke Toba[SUP] 2 3 [/SUP], Michihito Sasaki[SUP] 2 [/SUP], Yasuko Orba[SUP] 2 [/SUP], Hirofumi Sawa[SUP] 2 4 5 [/SUP], Akihiko Sato[SUP] 2 3 [/SUP], Eiji Kawanishi[SUP] 1 [/SUP], Akio Ojida[SUP] 1 [/SUP]
Affiliations
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 (3CL[SUP]pro[/SUP]) is a promising target for COVID-19 treatment. Here, we report a new class of covalent inhibitors of 3CL[SUP]pro[/SUP] 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 3CL[SUP]pro[/SUP]. The strong antiviral activity and favorable pharmacokinetic properties of YH-6 suggest its potential as a lead compound for the treatment of COVID-19.
. 2022 Oct 13.
doi: 10.1021/acs.jmedchem.2c01081. Online ahead of print.
Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease
Yuya Hirose[SUP] 1 [/SUP], Naoya Shindo[SUP] 1 [/SUP], Makiko Mori[SUP] 1 [/SUP], Satsuki Onitsuka[SUP] 1 [/SUP], Hikaru Isogai[SUP] 1 [/SUP], Rui Hamada[SUP] 1 [/SUP], Tadanari Hiramoto[SUP] 1 [/SUP], Jinta Ochi[SUP] 1 [/SUP], Daisuke Takahashi[SUP] 1 [/SUP], Tadashi Ueda[SUP] 1 [/SUP], Jose M M Caaveiro[SUP] 1 [/SUP], Yuya Yoshida[SUP] 1 [/SUP], Shigehiro Ohdo[SUP] 1 [/SUP], Naoya Matsunaga[SUP] 1 [/SUP], Shinsuke Toba[SUP] 2 3 [/SUP], Michihito Sasaki[SUP] 2 [/SUP], Yasuko Orba[SUP] 2 [/SUP], Hirofumi Sawa[SUP] 2 4 5 [/SUP], Akihiko Sato[SUP] 2 3 [/SUP], Eiji Kawanishi[SUP] 1 [/SUP], Akio Ojida[SUP] 1 [/SUP]
Affiliations
- PMID: 36229406
- DOI: 10.1021/acs.jmedchem.2c01081
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 (3CL[SUP]pro[/SUP]) is a promising target for COVID-19 treatment. Here, we report a new class of covalent inhibitors of 3CL[SUP]pro[/SUP] 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 3CL[SUP]pro[/SUP]. The strong antiviral activity and favorable pharmacokinetic properties of YH-6 suggest its potential as a lead compound for the treatment of COVID-19.