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

<div class='caption-title'>Intracellular concentrations of TKB245 and TKB248.</div>
<div class='caption-title'>In vivo efficacy of TKB245 and TKB248 against SARS-CoV-2NC928-2NOmicron_BA.1, SARS-CoV-2UW-5250Delta and SARS-CoV-2NCD1288Omicron_BA.2-infected hACE2-knocked-in mice.</div>
<div class='caption-title'>Native mass spectrometric analysis of SARS-CoV-2 Mpro-inhibitor interaction.</div>
Higashi-Kuwata N, Tsuji K, Hayashi H, Bulut H, Kiso M, Imai M, Ogata-Aoki H, Ishii T, Kobayakawa T, Nakano K, Takamune N, Kishimoto N, Hattori SI, Das D, Uemura Y, Shimizu Y, Aoki M, Hasegawa K, Suzuki S, Nishiyama A, Saruwatari J, Shimizu Y, Sukenaga Y, Takamatsu Y, Tsuchiya K, Maeda K, Yoshimura K, Iida S, Ozono S, Suzuki T, Okamura T, Misumi S, Kawaoka Y, Tamamura H, Mitsuya H
OpenAccess logo Nat Commun 14 1076 (2023)
Cited: 7 times
EuropePMC logo PMID: 36841831

Abstract

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 (Mpro) 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 Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro'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.

Reviews - 8dox mentioned but not cited (1)

  1. Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives. Citarella A, Dimasi A, Moi D, Passarella D, Scala A, Piperno A, Micale N. Biomolecules 13 1339 (2023)


Reviews citing this publication (3)

  1. Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs. Chandra G, Singh DV, Mahato GK, Patel S. Chem Zvesti 1-22 (2023)
  2. On the origins of SARS-CoV-2 main protease inhibitors. Janin YL. RSC Med Chem 15 81-118 (2024)
  3. Progress in SARS-CoV-2, diagnostic and clinical treatment of COVID-19. Li Y, Lu SM, Wang JL, Yao HP, Liang LG. Heliyon 10 e33179 (2024)

Articles citing this publication (3)



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