Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom.
J Med Chem. 2022 Apr 14;65(7):5606-5624. doi: 10.1021/acs.jmedchem.1c02104. Epub 2022 Mar 18.
African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites and is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both and via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.
非洲动物锥虫病或那加那病，主要由原生动物寄生虫 和 的感染引起，是撒哈拉以南非洲牛和其他牲畜的主要问题。目前的治疗方法受到药物耐药性的威胁，迫切需要新的、有效的药物。在这里，我们报告了最初开发用于治疗人类非洲锥虫病的化合物系列的再定位。一个专注于开发更具溶解性类似物的药物化学计划，导致了一种能够通过静脉给药治愈感染 和 的牛的先导化合物的开发。进一步的优化有可能为这种疾病提供一种单次肌肉内治疗。综合作用模式研究表明，这种有前途的化合物和相关类似物的分子靶标是细胞周期蛋白依赖性激酶 CRK12。
