tetano
Editor, Senior Moderator
Antiviral Res
. 2023 Mar 28;105586.
doi: 10.1016/j.antiviral.2023.105586. Online ahead of print.
Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2
Yujian Yang[SUP] 1 [/SUP], Liu Cao[SUP] 2 [/SUP], Ming Yan[SUP] 3 [/SUP], Jun Zhou[SUP] 1 [/SUP], Sidi Yang[SUP] 4 [/SUP], Tiefeng Xu[SUP] 2 [/SUP], Siyao Huang[SUP] 2 [/SUP], Kun Li[SUP] 2 [/SUP], Qifan Zhou[SUP] 1 [/SUP], Guanguan Li[SUP] 1 [/SUP], Yujun Zhu[SUP] 5 [/SUP], Feng Cong[SUP] 5 [/SUP], Hongmin Zhang[SUP] 6 [/SUP], Deyin Guo[SUP] 7 [/SUP], Yingjun Li[SUP] 8 [/SUP], Xumu Zhang[SUP] 9 [/SUP]
Affiliations
Abstract
S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CL[SUP]pro[/SUP]) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11-d2-S-217622 compound YY-278 retained in vitro activity against 3CL[SUP]pro[/SUP] and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CL[SUP]pro[/SUP] with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278, as well as S-217622, displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases.
Keywords: 3-chymotrypsin-like protease; Coronavirus; Crystal structure; Deuterated drug; S-217622 (ensitrelvir); SARS-CoV-2.
. 2023 Mar 28;105586.
doi: 10.1016/j.antiviral.2023.105586. Online ahead of print.
Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2
Yujian Yang[SUP] 1 [/SUP], Liu Cao[SUP] 2 [/SUP], Ming Yan[SUP] 3 [/SUP], Jun Zhou[SUP] 1 [/SUP], Sidi Yang[SUP] 4 [/SUP], Tiefeng Xu[SUP] 2 [/SUP], Siyao Huang[SUP] 2 [/SUP], Kun Li[SUP] 2 [/SUP], Qifan Zhou[SUP] 1 [/SUP], Guanguan Li[SUP] 1 [/SUP], Yujun Zhu[SUP] 5 [/SUP], Feng Cong[SUP] 5 [/SUP], Hongmin Zhang[SUP] 6 [/SUP], Deyin Guo[SUP] 7 [/SUP], Yingjun Li[SUP] 8 [/SUP], Xumu Zhang[SUP] 9 [/SUP]
Affiliations
- PMID: 36997073
- DOI: 10.1016/j.antiviral.2023.105586
Abstract
S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CL[SUP]pro[/SUP]) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11-d2-S-217622 compound YY-278 retained in vitro activity against 3CL[SUP]pro[/SUP] and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CL[SUP]pro[/SUP] with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278, as well as S-217622, displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases.
Keywords: 3-chymotrypsin-like protease; Coronavirus; Crystal structure; Deuterated drug; S-217622 (ensitrelvir); SARS-CoV-2.