Opportunities for Partnering in Medicine, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom.
PLoS Negl Trop Dis. 2011 Apr 5;5(4):e1017. doi: 10.1371/journal.pntd.0001017.
Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3β (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK-3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/academic partnership facilitated by the World Health Organisation Tropical Diseases Research division (WHO TDR) was initiated to stimulate research aimed at identifying new drugs for treating HAT.
METHODOLOGY/PRINCIPAL FINDINGS: A subset of over 16,000 inhibitors of HsGSK-3 β from the Pfizer compound collection was screened against the shorter of two orthologues of TbruGSK-3. The resulting active compounds were tested for selectivity versus HsGSK-3β and a panel of human kinases, as well as in vitro anti-trypanosomal activity. Structural analysis of the human and trypanosomal enzymes was also performed.
CONCLUSIONS/SIGNIFICANCE: We identified potent and selective compounds representing potential attractive starting points for a drug discovery program. Structural analysis of the human and trypanosomal enzymes also revealed hypotheses for further improving selectivity of the compounds.
引起人类非洲锥虫病（HAT）的布氏锥虫表达两种与人糖原合酶激酶 3β（HsGSK-3）具有同源性的蛋白，分别命名为 TbruGSK-3 短和 TbruGSK-3 长。TbruGSK-3 短已被验证为潜在的药物靶点，由于该酶也被作为人类药物靶点进行研究，因此有大量的抑制剂可用于筛选寄生虫酶。世界卫生组织热带病研究司（WHO TDR）通过合作的产业/学术伙伴关系，启动了旨在寻找治疗 HAT 的新药的研究。
方法/主要发现：从辉瑞化合物库中筛选出超过 16000 种 HsGSK-3β抑制剂中的一部分，针对 TbruGSK-3 的两个同源物中的较短者进行筛选。对具有活性的化合物进行了针对 HsGSK-3β和一组人类激酶的选择性测试，以及体外抗锥虫活性测试。还对人和锥虫酶进行了结构分析。
结论/意义：我们鉴定了具有潜在吸引力的药物发现计划的起始点的有效且具有选择性的化合物。对人和锥虫酶的结构分析也为进一步提高化合物的选择性提供了假设。
