Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2

• Published in: Nature communications Vol. 14; no. 1; pp. 1076 - 13
• Main Authors: Higashi-Kuwata, Nobuyo, Tsuji, Kohei, Hayashi, Hironori, Bulut, Haydar, Kiso, Maki, Imai, Masaki, Ogata-Aoki, Hiromi, Ishii, Takahiro, Kobayakawa, Takuya, Nakano, Kenta, Takamune, Nobutoki, Kishimoto, Naoki, Hattori, Shin-ichiro, Das, Debananda, Uemura, Yukari, Shimizu, Yosuke, Aoki, Manabu, Hasegawa, Kazuya, Suzuki, Satoshi, Nishiyama, Akie, Saruwatari, Junji, Shimizu, Yukiko, Sukenaga, Yoshikazu, Takamatsu, Yuki, Tsuchiya, Kiyoto, Maeda, Kenji, Yoshimura, Kazuhisa, Iida, Shun, Ozono, Seiya, Suzuki, Tadaki, Okamura, Tadashi, Misumi, Shogo, Kawaoka, Yoshihiro, Tamamura, Hirokazu, Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 631/154/309; 631/326/22/1295; 631/326/596/4130; 631/45/468; ACE2; Amino acids; Angiotensin-converting enzyme 2; Antiviral agents; Antiviral drugs; Benzothiazole; Coronaviruses; Covalent bonds; COVID-19; Crystallography; Dimerization; Enzymatic activity; Fluorine; Humanities and Social Sciences; Infectivity; multidisciplinary; Optimization; Protease; Public health; Replication; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spectrometry
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36729-0

COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (M pro ) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer M pro , apparently promoting M pro dimerization. X-ray crystallographic analysis shows that both compounds bind to M pro ’s active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics. Effective antivirals are critical for combatting SARS-CoV-2 infections. Here, the authors develop two orally available small molecules, which specifically inhibit the activity of the SARS-CoV-2 main protease and potently block the infectivity and replication of various SARS-CoV-2 strains in cells and mice.