Open AccessGRL-0920, an Indole Chloropyridinyl Ester, Completely Blocks SARS-CoV-2 Infection
Author(s) -
Shin-ichiro Hattori,
Nobuyo Higshi-Kuwata,
Jakka Raghavaiah,
Debananda Das,
Haydar Bulut,
David A. Davis,
Yuki Takamatsu,
Kouki Matsuda,
Nobutoki Takamune,
Naoki Kishimoto,
Tadashi Okamura,
Shogo Misumi,
Robert Yarchoan,
Kenji Maeda,
Arun K. Ghosh,
Hiroaki Mitsuya
Publication year - 2020
Publication title -
mbio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.562
H-Index - 121
eISSN - 2161-2129
pISSN - 2150-7511
DOI - 10.1128/mbio.01833-20
Subject(s) - chemistry , lopinavir , protease , vero cell , indole test , nitazoxanide , virology , enzyme , virus , biochemistry , biology , in vitro , viral load , immunology , antiretroviral therapy
Targeting the main protease (Mpro ) of SARS-CoV-2, we identified two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, active against SARS-CoV-2, employing RNA-qPCR and immunocytochemistry and show that the two compounds exerted potent activity against SARS-CoV-2. While GRL-0820 and remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred as examined with immunocytochemistry. In contrast, GRL-0920 completely blocked the infectivity and cytopathic effect of SARS-CoV-2 without significant toxicity. Structural modeling showed that indole and chloropyridinyl of the derivatives interacted with two catalytic dyad residues of Mpro , Cys145 and His41, resulting in covalent bonding, which was verified using HPLC/MS. The present data should shed light on the development of therapeutics for COVID-19, and optimization of GRL-0920 based on the present data is essential to develop more-potent anti-SARS-CoV-2 compounds for treating COVID-19.