دورية أكاديمية
SC83288 is a clinical development candidate for the treatment of severe malaria
| العنوان: | SC83288 is a clinical development candidate for the treatment of severe malaria |
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| المؤلفون: | Pegoraro, Stefan, P, Duffey, Maëlle, P, Otto, Thomas D., Wang, Yulin, P, Rösemann, Roman, M, Baumgartner, Roland, M, Fehler, Stefanie K., Lucantoni, Leonardo, D, Avery, Vicky M., Moreno-Sabater, Alicia, P, Mazier, Dominique, P, Vial, Henri J., Strobl, Stefan, M, Sanchez, Cecilia P., Lanzer, Michael, P |
| المساهمون: | 4SC AG, Heidelberg University Hospital Heidelberg, German Centre for Infection Research (DZIF), Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute Cambridge, 4SC Discovery, Griffith University Brisbane, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | ISSN: 2041-1723. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2017 |
| المجموعة: | Université de Montpellier: HAL |
| مصطلحات موضوعية: | [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| الوصف: | International audience ; Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca2+ transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | hal-01478640; https://hal.sorbonne-universite.fr/hal-01478640Test; https://hal.sorbonne-universite.fr/hal-01478640/documentTest; https://hal.sorbonne-universite.fr/hal-01478640/file/ncomms14193.pdfTest |
| DOI: | 10.1038/ncomms14193 |
| الإتاحة: | https://doi.org/10.1038/ncomms14193Test https://hal.sorbonne-universite.fr/hal-01478640Test https://hal.sorbonne-universite.fr/hal-01478640/documentTest https://hal.sorbonne-universite.fr/hal-01478640/file/ncomms14193.pdfTest |
| حقوق: | http://creativecommons.org/licenses/byTest/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.5FCD981A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/ncomms14193 |
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