@article{a0c1aac29f704541949e488239ae4808,
title = "Molecular basis for hycanthone drug action in schistosome parasites",
abstract = "Hycanthone (HYC) is a retired drug formerly used to treat schistosomiasis caused by infection from Schistosoma mansoni and S. haematobium. Resistance to HYC was first observed in S. mansoni laboratory strains and in patients in the 1970s and the use of this drug was subsequently discontinued with the substitution of praziquantel (PZQ) as the single antischistosomal drug in the worldwide formulary. In endemic regions, multiple organizations have partnered with the World Health Organization to deliver PZQ for morbidity control and prevention. While the monotherapy reduces the disease burden, additional drugs are needed to use in combination with PZQ to stay ahead of potential drug resistance. HYC will not be reintroduced into the schistosomiasis drug formulary as a combination drug because it was shown to have adverse properties including mutagenic, teratogenic and carcinogenic activities. Oxamniquine (OXA) was used to treat S. mansoni infection in Brazil during the brief period of HYC use, until the 1990s. Its antischistosomal efficacy has been shown to work through the same mechanism as HYC and it does not possess the undesirable properties linked to HYC. OXA demonstrates cross-resistance in Schistosoma strains with HYC resistance and both are prodrugs requiring metabolic activation in the worm to toxic sulfated forms. The target activating enzyme has been identified as a sulfotransferase enzyme and is currently used as the basis for a structure-guided drug design program. Here, we characterize the sulfotransferases from S. mansoni and S. haematobium in complexes with HYC to compare and contrast with OXA-bound sulfotransferase crystal structures. Although HYC is discontinued for antischistosomal treatment, it can serve as a resource for design of derivative compounds without contraindication.",
keywords = "Drug mechanism, Drug resistance, Hycanthone, Oxamniquine, Schistosoma haematobium, Schistosoma japonicum, Schistosoma mansoni, Schistosomiasis, Sulfotransferase",
author = "Meghan Guzman and Anastasia Rugel and Tarpley, {Reid S.} and Xiaohang Cao and McHardy, {Stanton F.} and LoVerde, {Philip T.} and Taylor, {Alexander B.}",
note = "Funding Information: The research was supported by a grant to P.T.L. and subcontract to S.F.M. from the National Institutes of Health (NIH, NIAID R01 AI115691). Schistosoma japonicum exposed Oncomelania hupensis were provided by the NIAID Schistosomiasis Resource Center of the Biomedical Research Institute (Rockville, MD) through NIH-NIAID Contract HHSN272201700014I for distribution through BEI Resources. The X-ray Crystallography Core Laboratory is a part of the Institutional Research Cores at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) supported by the Office of the Vice President for Research and the Mays Cancer Center (NIH P30 CA054174). We thank Dr. Chad A. Brautigam at The University of Texas Southwestern Medical Center at Dallas Macromolecular Biophysics Resource for assistance with microscale thermophoresis experiments. We gratefully acknowledge the Greehey Children's Cancer Institute RNAi High Throughput Screening Facility (UT Health San Antonio) for providing access to the NanoTemper Monolith MST system. This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P30 GM124165). The Eiger 16 M detector on 24-ID-E beam line is funded by a NIH-ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The research was supported by a grant to P.T.L. and subcontract to S.F.M. from the National Institutes of Health ( N IH, NIAID R01 AI115691) . Schistosoma japonicum exposed Oncomelania hupensis were provided by the NIAID Schistosomiasis Resource Center of the Biomedical Research Institute (Rockville, MD) through NIH-NIAID Contract HHSN272201700014I for distribution through BEI Resources. The X-ray Crystallography Core Laboratory is a part of the Institutional Research Cores at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) supported by the Office of the Vice President for Research and the Mays Cancer Center ( NIH P30 CA054174 ). We thank Dr. Chad A. Brautigam at The University of Texas Southwestern Medical Center at Dallas Macromolecular Biophysics Resource for assistance with microscale thermophoresis experiments. We gratefully acknowledge the Greehey Children{\textquoteright}s Cancer Institute RNAi High Throughput Screening Facility (UT Health San Antonio) for providing access to the NanoTemper Monolith MST system. This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health ( P30 GM124165 ). The Eiger 16 M detector on 24-ID-E beam line is funded by a NIH-ORIP HEI grant ( S10OD021527 ). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = mar,
doi = "10.1016/j.molbiopara.2020.111257",
language = "English (US)",
volume = "236",
journal = "Molecular and Biochemical Parasitology",
issn = "0166-6851",
publisher = "Elsevier",
}