SC83288 is a clinical development candidate for the treatment of severe malaria
Identifieur interne : 004242 ( Ncbi/Curation ); précédent : 004241; suivant : 004243SC83288 is a clinical development candidate for the treatment of severe malaria
Auteurs : Stefano Pegoraro [Allemagne] ; Maëlle Duffey [Allemagne] ; Thomas D. Otto [Royaume-Uni] ; Yulin Wang [Allemagne] ; Roman Rösemann [Allemagne] ; Roland Baumgartner [Allemagne] ; Stefanie K. Fehler [Allemagne] ; Leonardo Lucantoni [Australie] ; Vicky M. Avery [Australie] ; Alicia Moreno-Sabater [France] ; Dominique Mazier [France] ; Henri J. Vial [France] ; Stefan Strobl [Allemagne] ; Cecilia P. Sanchez [Allemagne] ; Michael Lanzer [Allemagne]Source :
- Nature Communications [ 2041-1723 ] ; 2017.
Abstract
Severe malaria is a life-threatening complication of an infection with the protozoan parasite
Url:
DOI: 10.1038/ncomms14193
PubMed: 28139658
PubMed Central: 5290327
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PMC:5290327Le document en format XML
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</affiliation>
</author>
<author><name sortKey="Lanzer, Michael" sort="Lanzer, Michael" uniqKey="Lanzer M" first="Michael" last="Lanzer">Michael Lanzer</name>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg</institution>
, Im Neuenheimer Feld 324, 69120 Heidelberg,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>German Center for Infection Research (DZIF), partner site Heidelberg</institution>
, 69120 Heidelberg,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature Communications</title>
<idno type="eISSN">2041-1723</idno>
<imprint><date when="2017">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Severe malaria is a life-threatening complication of an infection with the protozoan parasite <italic>Plasmodium falciparum</italic>
, 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 <italic>P. falciparum</italic>
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 Ca<sup>2+</sup>
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.</p>
</div>
</front>
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