An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans

Meghan A. Guzman, Anastasia R. Rugel, Reid S. Tarpley, Sevan N. Alwan, Frédéric D. Chevalier, Dmytro P. Kovalskyy, Xiaohang Cao, Stephen P. Holloway, Timothy J.C. Anderson, Alexander B. Taylor, Stanton F. McHardy, Philip T. Loverde

Producción científica: Articlerevisión exhaustiva

8 Citas (Scopus)


Currently there is only one method of treatment for human schistosomiasis, the drug prazi-quantel. Strong selective pressure has caused a serious concern for a rise in resistance to praziquantel leading to the necessity for additional pharmaceuticals, with a distinctly different mechanism of action, to be used in combination therapy with praziquantel. Previous treatment of Schistosoma mansoni included the use of oxamniquine (OXA), a prodrug that is enzymatically activated in S. mansoni but is ineffective against S. haematobium and S. japonicum. The oxamniquine activating enzyme was identified as a S. mansoni sulfotrans-ferase (SmSULT-OR). Structural data have allowed for directed drug development in reen-gineering oxamniquine to be effective against S. haematobium and S. japonicum. Guided by data from X-ray crystallographic studies and Schistosoma worm killing assays on oxam-niquine, our structure-based drug design approach produced a robust SAR program that tested over 300 derivatives and identified several new lead compounds with effective worm killing in vitro. Previous studies resulted in the discovery of compound CIDD-0066790, which demonstrated broad-species activity in killing of schistosome species. As these compounds are racemic mixtures, we tested and demonstrate that the R enantiomer CIDD-007229 kills S. mansoni, S. haematobium and S. japonicum better than the parent drug (CIDD-0066790). The search for derivatives that kill better than CIDD-0066790 has resulted in a derivative (CIDD-149830) that kills 100% of S. mansoni, S. haematobium and S. japonicum adult worms within 7 days. We hypothesize that the difference in activation and thus killing by the derivatives is due to the ability of the derivative to fit in the binding pocket of each sulfotransferase (SmSULT-OR, ShSULT-OR, SjSULT-OR) and to be efficiently sul-fated. The purpose of this research is to develop a second drug to be used in conjunction with praziquantel to treat the major human species of Schistosoma. Collectively, our findings show that CIDD-00149830 and CIDD-0072229 are promising novel drugs for the treatment of human schistosomiasis and strongly support further development and in vivo testing.

Idioma originalEnglish (US)
Número de artículoe0008517
Páginas (desde-hasta)1-17
Número de páginas17
PublicaciónPLoS Neglected Tropical Diseases
EstadoPublished - ago 2020
Publicado de forma externa

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases


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