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Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.
LaMonte, Gregory M; Rocamora, Frances; Marapana, Danushka S; Gnädig, Nina F; Ottilie, Sabine; Luth, Madeline R; Worgall, Tilla S; Goldgof, Gregory M; Mohunlal, Roxanne; Santha Kumar, T R; Thompson, Jennifer K; Vigil, Edgar; Yang, Jennifer; Hutson, Dylan; Johnson, Trevor; Huang, Jianbo; Williams, Roy M; Zou, Bing Yu; Cheung, Andrea L; Kumar, Prianka; Egan, Timothy J; Lee, Marcus C S; Siegel, Dionicio; Cowman, Alan F; Fidock, David A; Winzeler, Elizabeth A.
Afiliação
  • LaMonte GM; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Rocamora F; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Marapana DS; Division of Infection and Immunity, Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, 3052, Australia.
  • Gnädig NF; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
  • Ottilie S; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • Luth MR; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Worgall TS; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Goldgof GM; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • Mohunlal R; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Santha Kumar TR; Department of Laboratory Medicine, University of California, San Francisco, CA, 94143, USA.
  • Thompson JK; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • Vigil E; Department of Chemistry, University of Cape Town, Rondebosch, 7700, South Africa.
  • Yang J; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • Hutson D; Division of Infection and Immunity, Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, 3052, Australia.
  • Johnson T; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
  • Huang J; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Williams RM; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Zou BY; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Cheung AL; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Kumar P; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Egan TJ; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Lee MCS; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Siegel D; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Cowman AF; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
  • Fidock DA; Department of Chemistry, University of Cape Town, Rondebosch, 7700, South Africa.
  • Winzeler EA; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7700, South Africa.
Nat Commun ; 11(1): 1780, 2020 04 14.
Article em En | MEDLINE | ID: mdl-32286267
ABSTRACT
A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Antimaláricos Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Antimaláricos Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article