Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Nat Commun. 2023 Feb 25;14(1):1076. 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) 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, apparently promoting M dimerization. X-ray crystallographic analysis shows that both compounds bind to M'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.
由 SARS-CoV-2 引起的 COVID-19 一直是全球公共卫生的严重威胁。虽然目前有一些抗 SARS-CoV-2 的治疗方法，但它们的抗病毒效力还不够。在这里，我们鉴定出两种可口服的含有 4-氟苯并噻唑的小分子 TKB245 和 TKB248，它们特异性地抑制 SARS-CoV-2 的主要蛋白酶（M）的酶活性，并在基于细胞的测定中比尼马特韦、莫努匹韦和恩赛特韦更有效地阻断各种 SARS-CoV-2 株的感染性和复制，这些测定使用了各种靶细胞。这两种化合物还能阻断德尔塔和奥密克戎变异株在人 ACE2 敲入小鼠中的复制。天然质谱分析表明，这两种化合物都与二聚体 M 结合，显然促进了 M 的二聚化。X 射线晶体学分析表明，这两种化合物都结合到 M 的活性位点腔中，与催化氨基酸 Cys-145 形成共价键，苯并噻唑部分的 4-氟指向溶剂。这些数据表明，TKB245 和 TKB248 可能成为 COVID-19 的潜在治疗药物，并为进一步优化开发更有效和更安全的抗 SARS-CoV-2 治疗药物提供了线索。
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