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

Celia Miguel-Blanco, James M. Murithi, Ernest Diez Benavente, Fiona Angrisano, Katarzyna A. Sala, Donelly A. van Schalkwyk, Manu Vanaerschot, Frank Schwach, Matthew J. Fuchter, Oliver Billker, Colin J. Sutherland, Susana G. Campino, Taane G. Clark, Andrew M. Blagborough, David A. Fidock, Esperanza Herreros, Francisco Javier Gamo, Jake Baum, Michael J. Delves*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1888
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by funding from the Bill & Melinda Gates Foundation (Grant OPP1043501) and Medicines for Malaria Venture (Grant MMV08/2800). MJD acknowledges funding support from the Wellcome Trust ISSF fund. JB is supported by an Investigator Award from the Wellcome Trust (100993/Z/13/Z). SC is funded by BloomsburySET, Medical Research Council UK (MR/M01360X/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant no. BB/R013063/1) grants. TGC is funded by the Medical Research Council UK (Grant no. MR/ M01360X/1, MR/N010469/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant no. BB/R013063/1). AMB thanks the MRC (MR/N00227X/1), Isaac Newton Trust, Alborada Fund, Wellcome Trust ISSF and University of Cambridge JRG Scheme, GHIT and the Royal Society for funding. DAF acknowledges funding support from the Bill & Melinda Gates Foundation (Malaria Drug Accelerator Consortium, PI Dr. Elizabeth Winzeler). CJS is supported by Public Health England, the UK Medical Research Council and the European Developing Countries Trials Platform. DAvS was funded by the Medicines for Malaria Venture Grant RD/15/0017. OB received funding from a Wellcome core Grant 206194/Z/17/Z to the Sanger Institute.

Publisher Copyright:
© 2021, The Author(s).

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