Novartis Institute for Tropical Diseases, Emeryville, CA, USA.
Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
Science. 2023 Jun 30;380(6652):1349-1356. doi: 10.1126/science.adh0614. Epub 2023 Jun 29.
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.
生活在拉丁美洲和撒哈拉以南非洲的数百万人面临锥体虫感染的风险，这种感染会导致恰加斯病和非洲人类锥虫病（HAT）。虽然有更好的 HAT 治疗方法，但恰加斯病的治疗方法依赖于两种硝异喹啉，它们存在药物治疗方案冗长和安全性问题，导致频繁停药。我们针对锥虫进行了表型筛选，发现了一类氰基三唑（CT），它们在体外和恰加斯病和 HAT 的小鼠模型中均具有强大的杀锥虫活性。低温电子显微镜方法证实，CT 化合物通过选择性、不可逆地抑制锥虫拓扑异构酶 II，稳定双链 DNA：酶切割复合物来发挥作用。这些发现为成功治疗恰加斯病提供了一种潜在的治疗方法。
