Discovery Biology, Eskitis Institute (N27), Griffith University, Brisbane, 4111, Australia.
Expert Opin Drug Discov. 2013 May;8(5):495-507. doi: 10.1517/17460441.2013.783816. Epub 2013 Mar 31.
Human African trypanosomiasis (HAT) occurs as a result of infection with the protozoan parasites Trypanosoma brucei gambiense and T.b. rhodesiense and is nearly always fatal without treatment. However, current therapeutic options are severely limited and there is a desperate need for new compounds to treat the disease. Whole-cell high-throughput screening (HTS) is a technique frequently used to identify compounds with trypanocidal activity.
The authors examine the development of whole-organism HTS assays for T.b. brucei. The authors describe the successes achieved through HTS and discuss the advantages and disadvantages of whole-organism HTS.
Despite hundreds of trypanocidal molecules being identified by whole-organism HTS, very few have progressed into preclinical development. The failure of molecules identified by HTS to progress along the drug development pathway is due to a multitude of factors including undrug-like molecules and molecules having poor pharmacodynamics/kinetic properties. Future studies should focus on screening libraries that contain drug-like molecules that possess some of the properties required in the final compound.
人体感染布氏锥虫冈比亚亚种和布氏锥虫罗得西亚种会引发非洲人类锥虫病（HAT），如果不治疗，该病几乎总是致命的。然而，目前的治疗选择受到严重限制，迫切需要新的化合物来治疗这种疾病。全细胞高通量筛选（HTS）是一种常用于鉴定具有杀锥虫活性的化合物的技术。
作者检查了用于布氏锥虫的全器官 HTS 测定的开发。作者描述了通过 HTS 取得的成功，并讨论了全器官 HTS 的优缺点。
尽管通过全细胞 HTS 鉴定了数百种杀锥虫分子，但很少有分子能进展到临床前开发阶段。通过 HTS 鉴定的分子未能沿着药物开发途径进展的原因有很多，包括非药物样分子和具有差的药效动力学/动力学特性的分子。未来的研究应集中在筛选包含具有最终化合物所需某些特性的药物样分子的文库上。
