Two approaches to discovering and developing new drugs for Chagas disease

Memórias do Instituto Oswaldo Cruz

Jh Mckerrow¹  Ps Doyle¹  Jc Engel¹  Lm Podust¹  Sa Robertson¹  R Ferreira¹  T Saxton¹  M Arkin¹  Id Kerr¹  Ls Brinen¹  Cs Craik¹ 

[1] ,University of California Sandler Center at Mission Bay San Francisco CA ,USA

关键词: Chagas;    T. cruzi;    drug;    protease inhibitor;    CYP51;    HTS screen;    amastigote;   

DOI  :  10.1590/S0074-02762009000900034

来源: SciELO

【 摘 要 】

This review will focus on two general approaches carried out at the Sandler Center, University of California, San Francisco, to address the challenge of developing new drugs for the treatment of Chagas disease. The first approach is target-based drug discovery, and two specific targets, cytochrome P450 CYP51 and cruzain (aka cruzipain), are discussed. A "proof of concept" molecule, the vinyl sulfone inhibitor K777, is now a clinical candidate. The preclinical assessment compliance for filing as an Investigational New Drug with the United States Food and Drug Administration (FDA) is presented, and an outline of potential clinical trials is given. The second approach to identifying new drug leads is parasite phenotypic screens in culture. The development of an assay allowing high throughput screening of Trypanosoma cruzi amastigotes in skeletal muscle cells is presented. This screen has the advantage of not requiring specific strains of parasites, so it could be used with field isolates, drug resistant strains or laboratory strains. It is optimized for robotic liquid handling and has been validated through a screen of a library of FDA-approved drugs identifying 65 hits.

【 授权许可】

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