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  • SC83288 is a clinical development candidate for the treatment of severe malaria

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    Author(s)
    Pegoraro, Stefano
    Duffey, Maelle
    Otto, Thomas D
    Wang, Yulin
    Roesemann, Roman
    Baumgartner, Roland
    Fehler, Stefanie K
    Lucantoni, Leonardo
    Avery, Vicky M
    Moreno-Sabater, Alicia
    Mazier, Dominique
    Vial, Henri J
    Strobl, Stefan
    Sanchez, Cecilia P
    Lanzer, Michael
    Griffith University Author(s)
    Avery, Vicky M.
    Year published
    2017
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    Abstract
    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 ...
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    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.
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    Journal Title
    Nature Communications
    Volume
    8
    DOI
    https://doi.org/10.1038/ncomms14193
    Copyright Statement
    © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
    Subject
    Other biomedical and clinical sciences not elsewhere classified
    Other health sciences not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/342669
    Collection
    • Journal articles

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