Oxamniquine derivatives overcome praziquantel treatment limitations for schistosomiasis
Creators: name: Alwan, Sevan
name: Taylor, Alexander
name: Rhodes, Jayce
name: Tidwell, Michael
name: McHardy, Stanton
name: LoVerde, Philip
Publisher: name: Zenodo
Year: 2023
Subjects: Schistosoma
Drug discovery
Crystallography
Drug resistance
RNA interference (RNAi)

description: Human schistosomiasis is a neglected tropical disease caused by <em>S. mansoni, S. haematobium, </em>and <em>S. japonicum.</em> Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of <em>S. mansoni</em> included the use of Oxamniquine (OXA), a drug that activated by schistosomes' sulfotransferase (SULT). Guided by data from Xray crystallography and <em>Schistosoma </em>killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as powerful derivatives <em>in vitro</em> that kill (100%) of all three <em>Schistosoma</em> species at a final concentration of 143 µM. We evaluated the efficacy of the best OXA derivates in an <em>in vivo</em> model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against<em> S. mansoni</em>, CIDD-0149830 (80.2%) against <em>S. haematobium</em> and CIDD-066790 (86.7%) against <em>S. japonicum</em>. We have also evaluated the derivatives ability to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) of killing for all life stages at a final concentration of 143 µM <em>in vitro</em> and effective reduction in worm burden <em>in vivo</em>. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage of each PZQ and CIDD-0150303 reduced the worm burden in an animal model by (90.8%). Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are the novel drugs that overcome OXA limitation, and CIDD-0150303 can be used with PZQ in combination therapy.
description: Funding provided by: National Institute of General Medical Sciences<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000057<br>Award Number: 2k12GM111726Funding provided by: National Institute of Allergy and Infectious Diseases<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000060<br>Award Number: AI27219Funding provided by: National Institutes of Health<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000002<br>Award Number: P30 CA054174Funding provided by: NIH-ORIP SIG Grant *<br>Crossref Funder Registry ID: <br>Award Number: S10OD030374Funding provided by: National Institute of General Medical Sciences<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000057<br>Award Number: P30 GM124165Funding provided by: NIH-ORIP HEI *<br>Crossref Funder Registry ID: <br>Award Number: S10OD021527