Chemical and genetic validation of the statin drug target to treat the helminth disease, schistosomiasis.
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.
Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
Liliana
L
Rojo-Arreola
Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
Thavy
T
Long
Department of Computer Science, San Francisco State University, San Francisco, California, United States of America.
Dan
D
Asarnow
Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
Brian M
BM
Suzuki
Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America ; Department of Computer Science, San Francisco State University, San Francisco, California, United States of America.
Rahul
R
Singh
Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
Conor R
CR
Caffrey
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D055785:Gene Knockdown Techniques; D015801:Helminth Proteins / Q000096:biosynthesis / Q000235:genetics; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D058990:Molecular Targeted Therapy; D017035:Pravastatin / Q000494:pharmacology; D034622:RNA Interference; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D012555:Schistosomiasis mansoni / Q000188:drug therapy* / Q000469:parasitology; D019821:Simvastatin / Q000494:pharmacology*
D000871:Anthelmintics; D015801:Helminth Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D017035:Pravastatin; D008798:Mevalonic Acid