Discovery of Small-Molecule Allosteric Inhibitors of PfATC as Antimalarials

Chao Wang, Bidong Zhang, Arne Krüger, Xiaochen Du, Lydia Visser, Alex Dömling, Carsten Wrenger, Matthew Groves*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
59 Downloads (Pure)

Abstract

The discovery and development of new drugs against malaria remain urgent. Aspartate transcarbamoylase (ATC) has been suggested to be a promising target for antimalarial drug development. Here, we describe a series of small-molecule inhibitors of P. falciparum ATC with low nanomolar binding affinities that selectively bind to a previously unreported allosteric pocket, thereby inhibiting ATC activation. We demonstrate that the buried allosteric pocket is located close to the traditional ATC active site and that reported compounds maintain the active site of PfATC in its low substrate affinity/low activity conformation. These compounds inhibit parasite growth in blood stage cultures at single digit micromolar concentrations, whereas limited effects were seen against human normal lymphocytes. To our knowledge, this series represent the first PfATC-specific allosteric inhibitors.
Original languageEnglish
Pages (from-to)19070–19077
Number of pages8
JournalJournal of the American Chemical Society
Volume144
Issue number41
Early online date4-Oct-2022
DOIs
Publication statusPublished - 19-Oct-2022

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