SC83288 is a clinical development candidate for the treatment of severe malaria.
Identifieur interne : 000401 ( PubMed/Checkpoint ); précédent : 000400; suivant : 000402SC83288 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 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 Ca(2+) 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.
DOI: 10.1038/ncomms14193
PubMed: 28139658
Affiliations:
- Allemagne, Australie, France, Royaume-Uni
- Bade-Wurtemberg, District de Karlsruhe, Languedoc-Roussillon, Occitanie (région administrative)
- Heidelberg, Montpellier
- Université Montpellier 2
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Fehler</name><affiliation wicri:level="1"><nlm:affiliation>4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>4SC AG, Am Klopferspitz 19a, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Lucantoni, Leonardo" sort="Lucantoni, Leonardo" uniqKey="Lucantoni L" first="Leonardo" last="Lucantoni">Leonardo Lucantoni</name><affiliation wicri:level="1"><nlm:affiliation>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111</wicri:regionArea><wicri:noRegion>Nathan Queensland 4111</wicri:noRegion></affiliation></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name><affiliation wicri:level="1"><nlm:affiliation>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111</wicri:regionArea><wicri:noRegion>Nathan Queensland 4111</wicri:noRegion></affiliation></author><author><name sortKey="Moreno Sabater, Alicia" sort="Moreno Sabater, Alicia" uniqKey="Moreno Sabater A" first="Alicia" last="Moreno-Sabater">Alicia Moreno-Sabater</name><affiliation wicri:level="1"><nlm:affiliation>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, F-75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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, F-75013 Paris</wicri:regionArea><wicri:noRegion>75013 Paris</wicri:noRegion><wicri:noRegion>75013 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Mazier, Dominique" sort="Mazier, Dominique" uniqKey="Mazier D" first="Dominique" last="Mazier">Dominique Mazier</name><affiliation wicri:level="1"><nlm:affiliation>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, F-75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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, F-75013 Paris</wicri:regionArea><wicri:noRegion>75013 Paris</wicri:noRegion><wicri:noRegion>75013 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Vial, Henri J" sort="Vial, Henri J" uniqKey="Vial H" first="Henri J" last="Vial">Henri J. Vial</name><affiliation wicri:level="4"><nlm:affiliation>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, cc107, Place Eugène Bataillon, 34095 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, cc107, Place Eugène Bataillon, 34095 Montpellier</wicri:regionArea><wicri:noRegion>34095 Montpellier</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 2</orgName></affiliation></author><author><name sortKey="Strobl, Stefan" sort="Strobl, Stefan" uniqKey="Strobl S" first="Stefan" last="Strobl">Stefan Strobl</name><affiliation wicri:level="1"><nlm:affiliation>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Sanchez, Cecilia P" sort="Sanchez, Cecilia P" uniqKey="Sanchez C" first="Cecilia P" last="Sanchez">Cecilia P. Sanchez</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Lanzer, Michael" sort="Lanzer, Michael" uniqKey="Lanzer M" first="Michael" last="Lanzer">Michael Lanzer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28139658</idno><idno type="pmid">28139658</idno><idno type="doi">10.1038/ncomms14193</idno><idno type="wicri:Area/PubMed/Corpus">001211</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001211</idno><idno type="wicri:Area/PubMed/Curation">001200</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001200</idno><idno type="wicri:Area/PubMed/Checkpoint">001200</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001200</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">SC83288 is a clinical development candidate for the treatment of severe malaria.</title><author><name sortKey="Pegoraro, Stefano" sort="Pegoraro, Stefano" uniqKey="Pegoraro S" first="Stefano" last="Pegoraro">Stefano Pegoraro</name><affiliation wicri:level="1"><nlm:affiliation>4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>4SC AG, Am Klopferspitz 19a, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Duffey, Maelle" sort="Duffey, Maelle" uniqKey="Duffey M" first="Maëlle" last="Duffey">Maëlle Duffey</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Otto, Thomas D" sort="Otto, Thomas D" uniqKey="Otto T" first="Thomas D" last="Otto">Thomas D. Otto</name><affiliation wicri:level="1"><nlm:affiliation>Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA</wicri:regionArea><wicri:noRegion>Hinxton CB10 1SA</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Yulin" sort="Wang, Yulin" uniqKey="Wang Y" first="Yulin" last="Wang">Yulin Wang</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Rosemann, Roman" sort="Rosemann, Roman" uniqKey="Rosemann R" first="Roman" last="Rösemann">Roman Rösemann</name><affiliation wicri:level="1"><nlm:affiliation>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Baumgartner, Roland" sort="Baumgartner, Roland" uniqKey="Baumgartner R" first="Roland" last="Baumgartner">Roland Baumgartner</name><affiliation wicri:level="1"><nlm:affiliation>4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>4SC AG, Am Klopferspitz 19a, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Fehler, Stefanie K" sort="Fehler, Stefanie K" uniqKey="Fehler S" first="Stefanie K" last="Fehler">Stefanie K. Fehler</name><affiliation wicri:level="1"><nlm:affiliation>4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>4SC AG, Am Klopferspitz 19a, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Lucantoni, Leonardo" sort="Lucantoni, Leonardo" uniqKey="Lucantoni L" first="Leonardo" last="Lucantoni">Leonardo Lucantoni</name><affiliation wicri:level="1"><nlm:affiliation>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111</wicri:regionArea><wicri:noRegion>Nathan Queensland 4111</wicri:noRegion></affiliation></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name><affiliation wicri:level="1"><nlm:affiliation>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111</wicri:regionArea><wicri:noRegion>Nathan Queensland 4111</wicri:noRegion></affiliation></author><author><name sortKey="Moreno Sabater, Alicia" sort="Moreno Sabater, Alicia" uniqKey="Moreno Sabater A" first="Alicia" last="Moreno-Sabater">Alicia Moreno-Sabater</name><affiliation wicri:level="1"><nlm:affiliation>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, F-75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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, F-75013 Paris</wicri:regionArea><wicri:noRegion>75013 Paris</wicri:noRegion><wicri:noRegion>75013 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Mazier, Dominique" sort="Mazier, Dominique" uniqKey="Mazier D" first="Dominique" last="Mazier">Dominique Mazier</name><affiliation wicri:level="1"><nlm:affiliation>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, F-75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>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, F-75013 Paris</wicri:regionArea><wicri:noRegion>75013 Paris</wicri:noRegion><wicri:noRegion>75013 Paris</wicri:noRegion></affiliation></author><author><name sortKey="Vial, Henri J" sort="Vial, Henri J" uniqKey="Vial H" first="Henri J" last="Vial">Henri J. Vial</name><affiliation wicri:level="4"><nlm:affiliation>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, cc107, Place Eugène Bataillon, 34095 Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, cc107, Place Eugène Bataillon, 34095 Montpellier</wicri:regionArea><wicri:noRegion>34095 Montpellier</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 2</orgName></affiliation></author><author><name sortKey="Strobl, Stefan" sort="Strobl, Stefan" uniqKey="Strobl S" first="Stefan" last="Strobl">Stefan Strobl</name><affiliation wicri:level="1"><nlm:affiliation>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Sanchez, Cecilia P" sort="Sanchez, Cecilia P" uniqKey="Sanchez C" first="Cecilia P" last="Sanchez">Cecilia P. Sanchez</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Lanzer, Michael" sort="Lanzer, Michael" uniqKey="Lanzer M" first="Michael" last="Lanzer">Michael Lanzer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author></analytic><series><title level="j">Nature communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 Ca(2+) 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.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">28139658</PMID><DateCreated><Year>2017</Year><Month>01</Month><Day>31</Day></DateCreated><DateRevised><Year>2017</Year><Month>02</Month><Day>24</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2041-1723</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><PubDate><Year>2017</Year><Month>Jan</Month><Day>31</Day></PubDate></JournalIssue><Title>Nature communications</Title><ISOAbbreviation>Nat Commun</ISOAbbreviation></Journal><ArticleTitle>SC83288 is a clinical development candidate for the treatment of severe malaria.</ArticleTitle><Pagination><MedlinePgn>14193</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/ncomms14193</ELocationID><Abstract><AbstractText>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 Ca(2+) 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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pegoraro</LastName><ForeName>Stefano</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Duffey</LastName><ForeName>Maëlle</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Otto</LastName><ForeName>Thomas D</ForeName><Initials>TD</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-1246-7404</Identifier><AffiliationInfo><Affiliation>Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Yulin</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rösemann</LastName><ForeName>Roman</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baumgartner</LastName><ForeName>Roland</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fehler</LastName><ForeName>Stefanie K</ForeName><Initials>SK</Initials><AffiliationInfo><Affiliation>4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lucantoni</LastName><ForeName>Leonardo</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Avery</LastName><ForeName>Vicky M</ForeName><Initials>VM</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-4914-2299</Identifier><AffiliationInfo><Affiliation>Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Moreno-Sabater</LastName><ForeName>Alicia</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>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, F-75013 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie, F-75012 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mazier</LastName><ForeName>Dominique</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>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, F-75013 Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie-Mycologie, F-75013 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vial</LastName><ForeName>Henri J</ForeName><Initials>HJ</Initials><AffiliationInfo><Affiliation>Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, cc107, Place Eugène Bataillon, 34095 Montpellier, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Strobl</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sanchez</LastName><ForeName>Cecilia P</ForeName><Initials>CP</Initials><AffiliationInfo><Affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lanzer</LastName><ForeName>Michael</ForeName><Initials>M</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-0220-6526</Identifier><AffiliationInfo><Affiliation>Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), partner 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PubStatus="received"><Year>2016</Year><Month>06</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>12</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>2</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>2</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>2</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28139658</ArticleId><ArticleId IdType="pii">ncomms14193</ArticleId><ArticleId IdType="doi">10.1038/ncomms14193</ArticleId><ArticleId IdType="pmc">PMC5290327</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>Royaume-Uni</li></country><region><li>Bade-Wurtemberg</li><li>District de Karlsruhe</li><li>Languedoc-Roussillon</li><li>Occitanie (région administrative)</li></region><settlement><li>Heidelberg</li><li>Montpellier</li></settlement><orgName><li>Université Montpellier 2</li></orgName></list><tree><country name="Allemagne"><noRegion><name sortKey="Pegoraro, Stefano" sort="Pegoraro, Stefano" uniqKey="Pegoraro S" first="Stefano" last="Pegoraro">Stefano Pegoraro</name></noRegion><name sortKey="Baumgartner, Roland" sort="Baumgartner, Roland" uniqKey="Baumgartner R" first="Roland" last="Baumgartner">Roland Baumgartner</name><name sortKey="Duffey, Maelle" sort="Duffey, Maelle" uniqKey="Duffey M" first="Maëlle" last="Duffey">Maëlle Duffey</name><name sortKey="Fehler, Stefanie K" sort="Fehler, Stefanie K" uniqKey="Fehler S" first="Stefanie K" last="Fehler">Stefanie K. Fehler</name><name sortKey="Lanzer, Michael" sort="Lanzer, Michael" uniqKey="Lanzer M" first="Michael" last="Lanzer">Michael Lanzer</name><name sortKey="Rosemann, Roman" sort="Rosemann, Roman" uniqKey="Rosemann R" first="Roman" last="Rösemann">Roman Rösemann</name><name sortKey="Sanchez, Cecilia P" sort="Sanchez, Cecilia P" uniqKey="Sanchez C" first="Cecilia P" last="Sanchez">Cecilia P. Sanchez</name><name sortKey="Strobl, Stefan" sort="Strobl, Stefan" uniqKey="Strobl S" first="Stefan" last="Strobl">Stefan Strobl</name><name sortKey="Wang, Yulin" sort="Wang, Yulin" uniqKey="Wang Y" first="Yulin" last="Wang">Yulin Wang</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Otto, Thomas D" sort="Otto, Thomas D" uniqKey="Otto T" first="Thomas D" last="Otto">Thomas D. Otto</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Lucantoni, Leonardo" sort="Lucantoni, Leonardo" uniqKey="Lucantoni L" first="Leonardo" last="Lucantoni">Leonardo Lucantoni</name></noRegion><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name></country><country name="France"><noRegion><name sortKey="Moreno Sabater, Alicia" sort="Moreno Sabater, Alicia" uniqKey="Moreno Sabater A" first="Alicia" last="Moreno-Sabater">Alicia Moreno-Sabater</name></noRegion><name sortKey="Mazier, Dominique" sort="Mazier, Dominique" uniqKey="Mazier D" first="Dominique" last="Mazier">Dominique Mazier</name><name sortKey="Vial, Henri J" sort="Vial, Henri J" uniqKey="Vial H" first="Henri J" last="Vial">Henri J. Vial</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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