Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach.

Autor:	Buckner FS; Center for Emerging and Reemerging Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109, USA., Buchynskyy A; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Nagendar P; Department of Chemistry, University of Washington, Seattle, WA 98195, USA., Patrick DA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Gillespie JR; Center for Emerging and Reemerging Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109, USA., Herbst Z; Center for Emerging and Reemerging Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109, USA., Tidwell RR; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Gelb MH; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
Jazyk:	angličtina
Zdroj:	Tropical medicine and infectious disease [Trop Med Infect Dis] 2020 Feb 05; Vol. 5 (1). Date of Electronic Publication: 2020 Feb 05.
DOI:	10.3390/tropicalmed5010023
Abstrakt:	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. Competing Interests: The authors declare no conflicts of interest.
Databáze:	MEDLINE
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