Schistosomiasis, caused by a blood fluke, is a chronic, morbid and 'neglected'disease affecting as many as 700 million people globally. Ensuing anemia, abdominal pain, impaired physical and cognitive development degrade individual and societal productivity. Infection also elevates the risk of acquiring HIV, making treatment of schistosomiasis a priority for HIV-prevention. Treatment and control of schistosomiasis relies on just one drug, praziquantel (PZQ). Apart from concerns over possible drug resistance, PZQ has a number of failings. First, the standard oral dose of 40 mg/kg is rarely completely effective, with reported cure rates anywhere between 50 and 90%. Second, PZQ primarily kills adult parasites allowing immature worms to escape that upon maturation go on to generate morbidity. Third, PZQ is rapidly metabolized to a series of metabolites of which only one is partially as active as the parent molecule. In addition, the drug has a repellent taste and is marketed as a large 600 mg tablet making compliance, especially for children, difficult. The World Health Organization encourages the discovery and development of new drug candidates. The UCSF Center for Discovery and Innovation in Parasitic Diseases ( has identified commercial anti-hypercholesterolemia statin drugs - inhibitors of HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) - as potent schistosomicidal compounds. Statins first came to our attention during phenotypic whole-organism screens designed specifically to identify potential therapeutics for the schistosome parasite, screens that have now been adapted to quantitative, high-content imaging platforms. In advance of a detailed structure-activity lead optimization program to develop specific anti-schistosomal statins, we propose two Specific Aims. First, in partnership with an industry leader in statin drug development (Merck Sharp &Dohme Corp. (""""""""Merck"""""""")), we will employ quantitative and 'targeted'phenotypic screening of privileged statin libraries to obtain a preliminary understanding of the structural determinants of statin analogs that kill the parasite in vitro, including those that improve killing activity over commercial statins already tested. Secondly, we will optimize and standardize the recombinant expression of active Schistosoma mansoni HMGR, which will be central to deriving the kinetic and crystallographic data necessary to prosecute a subsequent lead optimization program to identify candidate molecules for treatment of schistosomiasis. The engagement of a large pharmaceutical company like Merck represents a watershed moment for schistosomiasis R&D since the discovery of PZQ 40 years ago. The combination of Merck's expertise in statin chemistry and UCSF's parasitological/screening expertise will short-list novel and more potent anti-schistosomal molecules. The proposed research activity is in advance of a collaborative and longer-term lead optimization program that will continue to utilize the tools employed or developed herein.

Public Health Relevance

Schistosomiasis is a tropical parasitic disease afflicting as many as 700 million people. Current therapy relies on just one drug and new drugs are needed. The current project is an academic-industrial partnership between UCSF and Merck Sharp &Dohme Corp. that will explore whether anti-hypercholesterolemia statin drugs and their derivatives are suitable for developing novel schistosomicidal drugs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Mcgugan, Glen C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Kyere-Davies, Gertrude; Agyare, Christian; Boakye, Yaw Duah et al. (2018) Effect of Phenotypic Screening of Extracts and Fractions of Erythrophleum ivorense Leaf and Stem Bark on Immature and Adult Stages of Schistosoma mansoni. J Parasitol Res 2018:9431467
Singh, Rahul; Beasley, Rachel; Long, Thavy et al. (2018) Algorithmic Mapping and Characterization of the Drug-Induced Phenotypic-Response Space of Parasites Causing Schistosomiasis. IEEE/ACM Trans Comput Biol Bioinform 15:469-481
Wolfe, Alan R; Neitz, R Jeffrey; Burlingame, Mark et al. (2018) TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling. Int J Parasitol Drugs Drug Resist 8:571-586
El-Sakkary, Nelly; Chen, Steven; Arkin, Michelle R et al. (2018) Octopamine signaling in the metazoan pathogen Schistosoma mansoni: localization, small-molecule screening and opportunities for drug development. Dis Model Mech 11:
Weeks, Janis C; Roberts, William M; Leasure, Caitlyn et al. (2018) Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing. Sci Rep 8:975
Long, Thavy; Neitz, R Jeffrey; Beasley, Rachel et al. (2016) Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. PLoS Negl Trop Dis 10:e0004356
Dvo?ák, Jan; Fajtová, Pavla; Ulrychová, Lenka et al. (2016) Excretion/secretion products from Schistosoma mansoni adults, eggs and schistosomula have unique peptidase specificity profiles. Biochimie 122:99-109
Glaser, Jan; Schurigt, Uta; Suzuki, Brian M et al. (2015) Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni. Molecules 20:10873-83
Asarnow, Daniel; Rojo-Arreola, Liliana; Suzuki, Brian M et al. (2015) The QDREC web server: determining dose-response characteristics of complex macroparasites in phenotypic drug screens. Bioinformatics 31:1515-8
Fonseca, Nayara Cristina; da Cruz, Luana Faria; da Silva Villela, Filipe et al. (2015) Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1. Antimicrob Agents Chemother 59:2666-77

Showing the most recent 10 out of 11 publications