Tsuji Kohei, Ishii Takahiro, Kobayakawa Takuya, Higashi-Kuwata Nobuyo, Azuma Chika, Nakayama Miyuki, Onishi Takato, Nakano Hiroki, Wada Naoya, Hori Miki, Shinohara Kouki, Miura Yutaro, Kawada Takuma, Hayashi Hironori, Hattori Shin-Ichiro, Bulut Haydar, Das Debananda, Takamune Nobutoki, Kishimoto Naoki, Saruwatari Junji, Okamura Tadashi, Nakano Kenta, Misumi Shogo, Mitsuya Hiroaki, Tamamura Hirokazu
Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Chiyoda-ku, Tokyo 101-0062, Japan.
Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo 162-8655, Japan.
iScience. 2022 Nov 18;25(11):105365. doi: 10.1016/j.isci.2022.105365. Epub 2022 Nov 1.
Potent and biostable inhibitors of the main protease (M) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of M and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound is highly potent and blocks SARS-CoV-2 infection without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds ( and ), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds and its biostable derivative are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.
基于活性命中化合物5h设计并合成了强效且生物稳定的新型冠状病毒主要蛋白酶（M）抑制剂。我们的策略不仅包括在抑制剂分子中引入氟原子以增加对M口袋的结合亲和力和细胞膜通透性，还包括用替代结构取代可消化的酰胺键以提高化合物的生物稳定性。化合物 具有高效力，可阻断新型冠状病毒感染且无病毒突破。与相应的母体化合物相比，这些化合物（ 和 ）在P2-P1酰胺键中含有硫代酰胺替代物的衍生物在小鼠体内表现出明显更优的药代动力学。这些数据表明，化合物 和其生物稳定衍生物 是治疗新冠肺炎的潜在药物，并且用硫代酰胺替代结构取代可消化的酰胺键是一种有效的方法。
