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

Author

Listed:
  • Stefano Pegoraro

    (4SC AG, Am Klopferspitz 19a)

  • Maëlle Duffey

    (Parasitology, Universitätsklinikum Heidelberg
    German Center for Infection Research (DZIF), partner site Heidelberg)

  • Thomas D Otto

    (Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus)

  • Yulin Wang

    (Parasitology, Universitätsklinikum Heidelberg
    German Center for Infection Research (DZIF), partner site Heidelberg
    Present address: Department of Parasitology, College of Basic Medical Sciences, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, Liaoning 116044, China)

  • Roman Rösemann

    (4SC Discovery GmbH, Am Klopferspitz 19a)

  • Roland Baumgartner

    (4SC AG, Am Klopferspitz 19a)

  • Stefanie K Fehler

    (4SC AG, Am Klopferspitz 19a
    Parasitology, Universitätsklinikum Heidelberg
    German Center for Infection Research (DZIF), partner site Heidelberg)

  • Leonardo Lucantoni

    (Eskitis Institute for Drug Discovery, Griffith University, Don Young)

  • Vicky M Avery

    (Eskitis Institute for Drug Discovery, Griffith University, Don Young)

  • Alicia Moreno-Sabater

    (Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l’hôpital
    AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie)

  • Dominique Mazier

    (Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l’hôpital
    AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie-Mycologie)

  • Henri J Vial

    (Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II)

  • Stefan Strobl

    (4SC Discovery GmbH, Am Klopferspitz 19a)

  • Cecilia P Sanchez

    (Parasitology, Universitätsklinikum Heidelberg
    German Center for Infection Research (DZIF), partner site Heidelberg)

  • Michael Lanzer

    (Parasitology, Universitätsklinikum Heidelberg
    German Center for Infection Research (DZIF), partner site Heidelberg)

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 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.

Suggested Citation

  • Stefano Pegoraro & Maëlle Duffey & Thomas D Otto & Yulin Wang & Roman Rösemann & Roland Baumgartner & Stefanie K Fehler & Leonardo Lucantoni & Vicky M Avery & Alicia Moreno-Sabater & Dominique Mazier , 2017. "SC83288 is a clinical development candidate for the treatment of severe malaria," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14193
    DOI: 10.1038/ncomms14193
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