An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans.
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,...
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ftdoajarticles:oai:doaj.org/article:63cb9a6c7eed407f9070e62dc9bc98ef 2023-05-15T15:16:16+02:00 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 2020-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008517 https://doaj.org/article/63cb9a6c7eed407f9070e62dc9bc98ef EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008517 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008517 https://doaj.org/article/63cb9a6c7eed407f9070e62dc9bc98ef PLoS Neglected Tropical Diseases, Vol 14, Iss 8, p e0008517 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008517 2022-12-31T12:51:32Z 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 ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 8 e0008517 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 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 An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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 ... |
format |
Article in Journal/Newspaper |
author |
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 |
author_facet |
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 |
author_sort |
Meghan A Guzman |
title |
An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. |
title_short |
An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. |
title_full |
An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. |
title_fullStr |
An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. |
title_full_unstemmed |
An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. |
title_sort |
iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008517 https://doaj.org/article/63cb9a6c7eed407f9070e62dc9bc98ef |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 8, p e0008517 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008517 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008517 https://doaj.org/article/63cb9a6c7eed407f9070e62dc9bc98ef |
op_doi |
https://doi.org/10.1371/journal.pntd.0008517 |
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PLOS Neglected Tropical Diseases |
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14 |
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8 |
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e0008517 |
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