Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach

被引:7
作者
Buckner, Frederick S. [1 ]
Buchynskyy, Andriy [2 ]
Nagendar, Pendem [2 ]
Patrick, Donald A. [3 ]
Gillespie, J. Robert [1 ]
Herbst, Zackary [1 ]
Tidwell, Richard R. [3 ]
Gelb, Michael H. [2 ]
机构
[1] Univ Washington, Dept Med, Ctr Emerging & Reemerging Infect Dis, Seattle, WA 98109 USA
[2] Univ Washington, Dept Chem, Seattle, WA 98195 USA
[3] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
基金
美国国家卫生研究院;
关键词
Trypanosoma brucei; human African trypanosomiasis; drug discovery; high-throughput screening; blood-brain barrier; brain permeability; pharmacology; phenotypic drug screening; UREA DERIVATIVES;
D O I
10.3390/tropicalmed5010023
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis. Eleven scaffolds subsequently underwent hit-to-lead optimization using standard medicinal chemistry approaches. Over a period of six years in an academic setting, 1539 analogs to the 11 scaffolds were synthesized. Eight scaffolds were discontinued either due to insufficient improvement in antiparasitic activity (5), poor pharmacokinetic properties (2), or a slow (static) antiparasitic activity (1). Three scaffolds were optimized to the point of curing the acute and/or chronic T. brucei infection model in mice. The progress was accomplished without knowledge of the mechanism of action (MOA) for the compounds, although the MOA has been discovered in the interim for one compound series. Studies on the safety and toxicity of the compounds are planned to help select candidates for potential clinical development. This research demonstrates the power of the phenotypic drug discovery approach for neglected tropical diseases.
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页数:18
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