Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-81343-z
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Funding
- Bill & Melinda Gates Foundation [OPP1043501]
- Medicines for Malaria Venture [MMV08/2800]
- Wellcome Trust ISSF fund
- Investigator Award from the Wellcome Trust [100993/Z/13/Z]
- BloomsburySET
- Medical Research Council UK [MR/M01360X/1, MR/R025576/1, MR/R020973/1, MR/N010469/1]
- BBSRC [BB/R013063/1]
- MRC [MR/N00227X/1]
- Isaac Newton Trust
- Alborada Fund
- Wellcome Trust ISSF
- University of Cambridge JRG Scheme
- GHIT
- Royal Society
- Bill & Melinda Gates Foundation (Malaria Drug Accelerator Consortium)
- Public Health England
- UK Medical Research Council
- European Developing Countries Trials Platform
- Medicines for Malaria Venture Grant [RD/15/0017]
- Wellcome core Grant [206194/Z/17/Z]
- Wellcome Trust [100993/Z/13/Z] Funding Source: Wellcome Trust
- BBSRC [BB/R013063/1] Funding Source: UKRI
- MRC [MR/N00227X/1, MR/M01360X/1] Funding Source: UKRI
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New antimalarial therapeutics are urgently needed to combat emerging parasite and mosquito resistance. Intense drug screening efforts have identified promising new antimalarial molecules with novel modes of action to combat existing drug resistance.
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.
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