Rational approach to drug discovery for human schistosomiasis.

Autor:	LoVerde PT; Departments of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA; Pathology and Laboratory Medicine, The University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: loverde@uthscsa.edu., Alwan SN; Departments of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA., Taylor AB; Departments of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA., Rhodes J; Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX, USA., Chevalier FD; Program in Host-Pathogen Interactions, Texas Biomedical Research Institute, San Antonio, TX, USA., Anderson TJ; Program in Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USA., McHardy SF; Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX, USA.
Jazyk:	angličtina
Zdroj:	International journal for parasitology. Drugs and drug resistance [Int J Parasitol Drugs Drug Resist] 2021 Aug; Vol. 16, pp. 140-147. Date of Electronic Publication: 2021 Jun 04.
DOI:	10.1016/j.ijpddr.2021.05.002
Abstrakt:	Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice effective against all three major species of Schistosoma, praziquantel (PZQ). However, as with many monotherapies, evidence for resistance is emerging in the field and can be selected for in the laboratory. Previously used therapies include oxamniquine (OXA), but shortcomings such as drug resistance and affordability resulted in discontinuation. Employing a genetic, biochemical and molecular approach, a sulfotransferase (SULT-OR) was identified as responsible for OXA drug resistance. By crystallizing SmSULT- OR with OXA, the mode of action of OXA was determined. This information allowed a rational approach to novel drug design. Our team approach with schistosome biologists, medicinal chemists, structural biologists and geneticists has enabled us to develop and test novel drug derivatives of OXA to treat this disease. Using an iterative process for drug development, we have successfully identified derivatives that are effective against all three species of the parasite. One derivative CIDD-0149830 kills 100% of all three human schistosome species within 5 days. The goal is to generate a second therapeutic with a different mode of action that can be used in conjunction with praziquantel to overcome the ever-growing threat of resistance and improve efficacy. The ability and need to design, screen, and develop future, affordable therapeutics to treat human schistosomiasis is critical for successful control program outcomes. (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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