{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:19:50Z","timestamp":1790835590331,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011018","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T00:00:00Z","timestamp":1689811200000}}],"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T00:00:00Z","timestamp":1688947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["2k12GM111726"],"award-info":[{"award-number":["2k12GM111726"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI27219"],"award-info":[{"award-number":["AI27219"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021533","name":"Morrison Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021533","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA054174"],"award-info":[{"award-number":["P30 CA054174"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH-ORIP SIG","award":["S10OD030374"],"award-info":[{"award-number":["S10OD030374"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30 GM124165"],"award-info":[{"award-number":["P30 GM124165"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH-ORIP HEI","award":["S10OD021527"],"award-info":[{"award-number":["S10OD021527"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Human schistosomiasis is a neglected tropical disease caused by\n                    <jats:italic>Schistosoma mansoni<\/jats:italic>\n                    ,\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>haematobium<\/jats:italic>\n                    , and\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>japonicum<\/jats:italic>\n                    . 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\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mansoni<\/jats:italic>\n                    included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and\n                    <jats:italic>Schistosoma<\/jats:italic>\n                    killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150\n                    <jats:bold>610<\/jats:bold>\n                    and CIDD-0150\n                    <jats:bold>303<\/jats:bold>\n                    as potent derivatives\n                    <jats:italic>in vitro<\/jats:italic>\n                    that kill (100%) of all three\n                    <jats:italic>Schistosoma<\/jats:italic>\n                    species at a final concentration of 71.5 \u03bcM. We evaluated the efficacy of the best OXA derivates in an\n                    <jats:italic>in vivo<\/jats:italic>\n                    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 -150\n                    <jats:bold>303<\/jats:bold>\n                    (81.8%) against\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mansoni<\/jats:italic>\n                    , CIDD-0149\n                    <jats:bold>830<\/jats:bold>\n                    (80.2%) against\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>haematobium<\/jats:italic>\n                    and CIDD-066\n                    <jats:bold>790<\/jats:bold>\n                    (86.7%) against\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>japonicum<\/jats:italic>\n                    . We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150\n                    <jats:bold>303<\/jats:bold>\n                    demonstrated (100%) killing for all life stages at a final concentration of 143 \u03bcM\n                    <jats:italic>in vitro<\/jats:italic>\n                    and effective reduction in worm burden\n                    <jats:italic>in vivo<\/jats:italic>\n                    against\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mansoni<\/jats:italic>\n                    . To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150\n                    <jats:bold>303<\/jats:bold>\n                    and CIDD-0150\n                    <jats:bold>610<\/jats:bold>\n                    demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg\/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150\n                    <jats:bold>303<\/jats:bold>\n                    , CIDD-0149\n                    <jats:bold>830<\/jats:bold>\n                    and CIDD-066\n                    <jats:bold>790<\/jats:bold>\n                    are novel drugs that overcome some of PZQ limitations, and CIDD-0150\n                    <jats:bold>303<\/jats:bold>\n                    can be used with PZQ in combination therapy.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011018","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T14:00:51Z","timestamp":1688997651000},"page":"e1011018","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Oxamniquine derivatives overcome Praziquantel treatment limitations for Schistosomiasis"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-4859","authenticated-orcid":true,"given":"Sevan N.","family":"Alwan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander B.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayce","family":"Rhodes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Tidwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanton F.","family":"McHardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip T.","family":"LoVerde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,7,10]]},"reference":[{"issue":"9541","key":"ppat.1011018.ref001","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/S0140-6736(06)69440-3","article-title":"Human schistosomiasis.","volume":"368","author":"B Gryseels","year":"2006","journal-title":"Lancet"},{"issue":"7","key":"ppat.1011018.ref002","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S1473-3099(06)70521-7","article-title":"Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk.","volume":"6","author":"P Steinmann","year":"2006","journal-title":"Lancet Infect Dis."},{"key":"ppat.1011018.ref003","unstructured":"WHO. 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