Targeting Plasmodium falciparum IspD in the Methyl- d -erythritol Phosphate Pathway: Urea-Based Compounds with Nanomolar Potency on Target and Low-Micromolar Whole-Cell Activity
Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide The methyl- d -erythritol phosphate (MEP) pathway has emerged as an interesting target in the fight against antimicrobial resistance. The pathway is essential in many human pathogens, including Plasmodium falciparum ( Pf ), but is absent in human cells. In the present study, we report on the discovery of a new chemical class targeting IspD, the third enzyme in the pathway. Exploration of the structure–activity relationship yielded inhibitors with potency in the low-nanomolar range. Moreover, we investigated the whole-cell activity, mode of inhibition, metabolic, and plasma stability of this compound class, and conducted in vivo pharmacokinetic profiling on selected compounds. Lastly, we disclosed a new mass spectrometry (MS)-based enzymatic assay for direct IspD activity determination, circumventing the need for auxiliary enzymes. In summary, we have identified a readily synthesizable compound class, demonstrating excellent activity and a promising profile, positioning it as a valuable tool compound for advancing research on IspD.
Source: Journal of Medicinal Chemistry
Institutions: Helmholtz Centre for Infection Research, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Children's Hospital of Philadelphia, Swiss Tropical and Public Health Institute, University of Basel, Universität Hamburg, German Center for Infection Research, BASF (Germany), University of Pennsylvania
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Children's Hospital of Philadelphia, University of Pennsylvania, Universität Basel, Deutsches Zentrum für Infektionsforschung, European Commission, Universität des Saarlandes, Universität Hamburg, Università di Bologna, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, National Institute of Allergy and Infectious Diseases, H2020 Marie Skłodowska-Curie Actions
Awards: G1781501939, G2029682150, Exploiting the methylerythritol phosphate pathway as a source of drug targets for novel anti-infectives, G434337789, G5406749139, Exploiting the methylerythritol phosphate pathway as a source of drug targets for novel anti-infectives, MEP pathway resistance in Plasmodium falciparum
OpenAlex ID: W4402680571