Open AccessAn iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans
Author(s) -
Meghan A. Guzman,
Anastasia R. Rugel,
Reid S. Tarpley,
Sevan N. Alwan,
Frédéric D. Chevalier,
Dmytro Kovalskyy,
Xiaoguang Cao,
S. Holloway,
T Anderson,
Alexander B. Taylor,
Stanton F. McHardy,
Philip T. LoVerde
Publication year - 2020
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0008517
Subject(s) - oxamniquine , praziquantel , schistosoma mansoni , schistosoma japonicum , schistosomiasis , schistosoma haematobium , biology , drug , pharmacology , immunology , helminths
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 ( Sm SULT-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 ( Sm SULT-OR, Sh SULT-OR, Sj SULT-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.