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

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

doi:10.1371/journal.pntd.0008517

Abstract

Currently there is only one method of treatment for human schistosomiasis, the drug praziquantel. 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 sulfotransferase (SmSULT-OR). Structural data have allowed for directed drug development in reengineering oxamniquine to be effective against S. haematobium and S. japonicum. Guided by data from X-ray crystallographic studies and Schistosoma worm killing assays on oxamniquine, 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 sulfated. 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.

Highlights

Human schistosomiasis is caused by three major species: S. mansoni, S. haematobium, and S. japonicum
There is no effective vaccine against human schistosomiasis; there is a drug that is effective against all three major human schistosome species, praziquantel (PZQ)
Compounds derived from the structural data of OXA in the SmSULT-OR active site were designed, synthesized and initially tested in vitro for worm killing against OXA sensitive S. mansoni adult male worms [37]

Summary

Introduction

Human schistosomiasis is caused by three major species: S. mansoni, S. haematobium, and S. japonicum. Current estimates indicate that globally schistosomiasis affects over 229 million people in 78 countries [1,2,3] Of those infected, over 100 million are estimated to be symptomatic, 20 million experience long term complications due to infection, and anywhere from 20,000–200,000 people are estimated to die from the disease annually [4,5,6]. Over 100 million are estimated to be symptomatic, 20 million experience long term complications due to infection, and anywhere from 20,000–200,000 people are estimated to die from the disease annually [4,5,6] These three major species account for the vast majority of global burden [7,8,9,10]. The mainstay of schistosome control programs have used repeated mass chemotherapy with PZQ–currently 250 million doses per annum–of the at-risk and infected populations of human hosts [5, 11,12,13]

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