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  • Miguel-Blanco, CeliaGlobal Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain (author)

The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • 2021-01-21
  • Springer Nature,2021
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:umu-180515
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-180515URI
  • https://doi.org/10.1038/s41598-021-81343-zDOI

Supplementary language notes

  • Language:English
  • Summary in:English

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Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957—a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance.

Subject headings and genre

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  • Murithi, James M.Department of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Benavente, Ernest DiezDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom (author)
  • Angrisano, FionaDivision of Microbiology and Parasitology, Department of Pathology, Cambridge University, Tennis Court Road, Cambridge, United Kingdom (author)
  • Sala, Katarzyna A.Department of Life Sciences, Imperial College London, South Kensington, London, United Kingdom (author)
  • van Schalkwyk, Donelly A.Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom (author)
  • Vanaerschot, ManuDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Schwach, FrankParasites and Microbes Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom (author)
  • Fuchter, Matthew J.Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, Wood Lane, London, United Kingdom (author)
  • Billker, OliverUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet),Parasites and Microbes Programme, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK(Swepub:umu)olbi0005 (author)
  • Sutherland, Colin J.Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom (author)
  • Campino, Susana G.Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom (author)
  • Clark, Taane G.Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom (author)
  • Blagborough, Andrew M.Division of Microbiology and Parasitology, Department of Pathology, Cambridge University, Tennis Court Road, Cambridge, United Kingdom; Department of Life Sciences, Imperial College London, South Kensington, London, United Kingdom (author)
  • Fidock, David A.Department of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, NY, New York, United States (author)
  • Herreros, EsperanzaGlobal Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain; Medicines for Malaria Venture, 20 Route de Pré-Bois, Geneva 15, Switzerland (author)
  • Gamo, Francisco JavierGlobal Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain (author)
  • Baum, JakeDepartment of Life Sciences, Imperial College London, South Kensington, London, United Kingdom (author)
  • Delves, Michael J.Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom (author)
  • Global Health, GlaxoSmithKline, Tres Cantos, Madrid, SpainDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, NY, New York, United States (creator_code:org_t)

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  • In:Scientific Reports: Springer Nature11:12045-2322

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