Rational approach to drug discovery for human schistosomiasis

Philip T. LoVerde, Sevan N. Alwan, Alexander B. Taylor, Jayce Rhodes, Frédéric D. Chevalier, Timothy JC Anderson, Stanton F. McHardy

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)140-147
Number of pages8
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume16
DOIs
StatePublished - Aug 2021
Externally publishedYes

Keywords

  • Control programs
  • Drug discovery
  • Drug resistance
  • Oxamniquine
  • Schistosomiasis
  • Sulfotransferase

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases
  • Pharmacology (medical)

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