Journal article
Chemical and Genetic Validation of the Statin Drug Target to Treat the Helminth Disease, Schistosomiasis
PloS one, Vol.9(1), pp.e87594-e87594
01/29/2014
DOI: 10.1371/journal.pone.0087594
PMCID: PMC3906178
PMID: 24489942
Abstract
The mevalonate pathway is essential in eukaryotes and responsible for a diversity of fundamental synthetic activities. 3-hydroxy- 3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the pathway and is targeted by the ubiquitous statin drugs to treat hypercholesterolemia. Independent reports have indicated the cidal effects of statins against the flatworm parasite, S. mansoni, and the possibility that SmHMGR is a useful drug target to develop new statin-based anti-schistosome therapies. For six commercially available statins, we demonstrate concentration-and time-dependent killing of immature (somule) and adult S. mansoni in vitro at sub-micromolar and micromolar concentrations, respectively. Cidal activity trends with statin lipophilicity whereby simvastatin and pravastatin are the most and least active, respectively. Worm death is preventable by excess mevalonate, the product of HMGR. Statin activity against somules was quantified both manually and automatically using a new, machine learning-based automated algorithm with congruent results. In addition, to chemical targeting, RNA interference (RNAi) of HMGR also kills somules in vitro and, again, lethality is blocked by excess mevalonate. Further, RNAi of HMGR of somules in vitro subsequently limits parasite survival in a mouse model of infection by up to 80%. Parasite death, either via statins or specific RNAi of HMGR, is associated with activation of apoptotic caspase activity. Together, our genetic and chemical data confirm that S. mansoni HMGR is an essential gene and the relevant target of statin drugs. We discuss our findings in context of a potential drug development program and the desired product profile for a new schistosomiasis drug.
Details
- Title: Subtitle
- Chemical and Genetic Validation of the Statin Drug Target to Treat the Helminth Disease, Schistosomiasis
- Creators
- Liliana Rojo-Arreola - University of California, San FranciscoThavy Long - Univ Calif San Francisco, Dept Pathol, Ctr Discovery & Innovat Parasit Dis, San Francisco, CA 94140 USADan Asarnow - San Francisco State UniversityBrian M. Suzuki - University of California, San FranciscoRahul Singh - University of California, San FranciscoConor R. Caffrey - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.9(1), pp.e87594-e87594
- DOI
- 10.1371/journal.pone.0087594
- PMID
- 24489942
- PMCID
- PMC3906178
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library Science
- Number of pages
- 11
- Grant note
- R21AI107390 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) IIS 0644418 / National Science Foundation; National Science Foundation (NSF) 1R01AI089896; R21AI107390 / National Institute of Allergy And Infectious Diseases of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P30DK026743 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) UC MEXUS-CONACYT; Consejo Nacional de Ciencia y Tecnologia (CONACyT)
- Language
- English
- Date published
- 01/29/2014
- Academic Unit
- Computer Science
- Record Identifier
- 9984446538402771
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