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In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidine-based antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Subsequent enzyme inhibition assay identified 11 fragments displaying IC50 in the 28-695 μM range and selectivity for PfDHFR. In addition to the known pyrimidine, three new anti-PfDHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with PfDHFR, revealing a binding in the active site, in the vicinity of catalytic residues, which was confirmed by molecular docking on all fragment hits. Finally, comparison with similar non-hit fragments provides preliminary input on available growth vectors for future drug development.

Metal ion dyshomeostasis is hypothesized to play a role in the toxicity and aggregation of the amyloid beta (Aβ) peptide, contributing to Alzheimer's disease (AD) pathology. We report on the synthesis and metal complexation ability of three bidentate quinoline-triazole derivatives 3-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)propan-1-ol ( QOH ), 4-(2-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)morpholine ( QMorph ), and 4-(2-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)thiomorpholine ( QTMorph ). We further study the utility of these ligands to modulate Aβ peptide aggregation processes in the presence and absence of Cu 2 + ions. Ligand-peptide interactions were first investigated using both 2-D 1 H– 15 N band-selective optimized flip angle short transient heteronuclear multiple quantum correlation (SOFAST-HMQC) NMR spectroscopy and molecular modeling techniques, indicating interactions with glutamic acid (E3) and several residues in the hydrophobic region of Aβ. Native gel electrophoresis with western blotting along with transmission electron microscopy provided information on the ability of each ligand to modulate Aβ aggregation. While the ligands alone did not modify Aβ peptide aggregation at the 24 h timepoint, signifying relatively weak ligand-peptide interactions, the ligands did modify the aggregation profile of the peptide in the presence of stoichiometric and suprastoichiometric Cu. Interestingly, the thioether derivative QTMorph exhibited the most pronounced effect on peptide aggregation in the presence of Cu. Overall, the quinoline-triazole ligand series were shown to interact with the hydrophobic region of the Aβ peptide, and modulate the Cu-Aβ aggregation process.

International audience; Artificial metalloenzymes, with their high selectivity and specificity combined with a wide scope of reactivity and substrates, constitute an original approach for catalyst development. Different strategies have been proposed for their elaboration, proceeding from modification of natural enzymes using bioengineering methods to de novo protein design. Another bio-inspired methodology for the development of hybrid catalysts consists in the incorporation of coordination complexes into biomolecules, with the aim to upgrade their catalytic abilities. In these systems, the reaction performed by the naked catalyst is modulated by the well-defined structure of the host biomolecule. This conveys added value to the catalyst, such as enantioselectivity or chemoselectivity. DNA, apo-enzymes, proteins and peptides have been engaged in this approach, affording a wide diversity of reactivities and substrates. The resulting systems can then be improved by combined chemical and bioengineering optimization, allowing access to powerful catalysts. Because this approach can virtually be applied to any biomolecule or coordination complex, the elaboration of bio-based hybrid catalysts seems promising for advance in catalysis.