The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957
Murithi, James M.
Benavente, Ernest Diez
Sala, Katarzyna A.
van Schalkwyk, Donelly A.
Fuchter, Matthew J.
Sutherland, Colin J.
Campino, Susana G.
Clark, Taane G.
Blagborough, Andrew M.
Fidock, David A.
Gamo, Francisco Javier
Delves, Michael J.
Nature Publishing Group UK
MetadataShow full item record
Miguel-Blanco, C., Murithi, J. M., Benavente, E. D., Angrisano, F., Sala, K. A., van Schalkwyk, D. A., Vanaerschot, M., et al. (2021). The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957. Scientific Reports, 11 (1)https://doi.org/10.1038/s41598-021-81343-z
Funder: Public Health England; doi: https://doi.org/10.13039/501100002141
Funder: European Developing Countries Trials Platform
Funder: Isaac Newton Trust
Funder: Alborada Fund
Funder: Global Health Innovative Technology Fund; doi: https://doi.org/10.13039/501100013996
Funder: Royal Society
Abstract: 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.
Article, /692/699/255/1629, /631/154/309/2144, article
Bill and Melinda Gates Foundation (OPP1043501, Malaria Drug Accelerator Consortium, OPP1043501)
Medicines for Malaria Venture (RD/15/0017, MMV08/2800)
Wellcome Trust (206194/Z/17/Z, 100993/Z/13/Z, ISSF fund)
Research England (BloomsburySET)
Medical Research Council (MR/M01360X/1, MR/N00227X/1)
Biotechnology and Biological Sciences Research Council (BB/R013063/1)
University of Cambridge (JRG Scheme)
External DOI: https://doi.org/10.1038/s41598-021-81343-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/316547
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/