Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, AL, 35899, USA.
Department of Biology, College of Science, George Mason University, Fairfax, VA, 22030, USA.
Eur J Med Chem. 2024 Nov 15;278:116808. doi: 10.1016/j.ejmech.2024.116808. Epub 2024 Aug 30.
Chikungunya virus (CHIKV) is responsible for the most endemic alphavirus infections called Chikungunya. The endemicity of Chikungunya has increased over the past two decades, and it is a pathogen with pandemic potential. There is currently no approved direct-acting antiviral to treat the disease. As part of our antiviral drug discovery program focused on alphaviruses and the non-structural protein 2 protease, we discovered that J12 and J13 can inhibit CHIKV nsP2 protease and block the replication of CHIKV in cell cultures. Both compounds are metabolically stable to human liver microsomal and S9 enzymes. J13 has excellent oral bioavailability in pharmacokinetics studies in mice and ameliorated Chikungunya symptoms in preliminary efficacy studies in mice. J13 exhibited an excellent safety profile in in vitro safety pharmacology and off-target screening assays, making J13 and its analogs good candidates for drug development against Chikungunya.
基孔肯雅病毒（CHIKV）是引起基孔肯雅热的最常见的甲病毒属感染。过去二十年来，基孔肯雅热的流行范围不断扩大，而且它具有引发大流行的潜力。目前尚无批准的直接抗病毒药物来治疗这种疾病。作为我们专注于甲病毒和非结构蛋白 2 蛋白酶的抗病毒药物发现计划的一部分，我们发现 J12 和 J13 可以抑制 CHIKV nsP2 蛋白酶并阻断 CHIKV 在细胞培养物中的复制。这两种化合物在人肝微粒体和 S9 酶中代谢稳定。J13 在小鼠药代动力学研究中具有良好的口服生物利用度，并在小鼠初步疗效研究中改善了基孔肯雅症状。J13 在体外安全药理学和非靶标筛选测定中表现出极好的安全性，使 J13 及其类似物成为开发针对基孔肯雅病毒的药物的良好候选物。
