Leishmania infantum arginase: biochemical characterization and inhibition by naturally occurring phenolic substances.

Inhibition of Leishmania arginase leads to a decrease in parasite growth and infectivity and thus represents an attractive therapeutic strategy. We evaluated the inhibitory potential of selected naturally occurring phenolic substances on Leishmania infantum arginase (ARGLi) and investigated their antileishmanial activity in vivo. ARGLi exhibited a Vmax of 0.28 ± 0.016 mM/min and a Km of 5.1 ± 1.1 mM for L-arginine. The phenylpropanoids rosmarinic acid and caffeic acid (100 µM) showed percentages of inhibition of 71.48 ± 0.85% and 56.98 ± 5.51%, respectively. Moreover, rosmarinic acid and caffeic acid displayed the greatest effects against L. infantum with IC50 values of 57.3 ± 2.65 and 60.8 ± 11 µM for promastigotes, and 7.9 ± 1.7 and 21.9 ± 5.0 µM for intracellular amastigotes, respectively. Only caffeic acid significantly increased nitric oxide production by infected macrophages. Altogether, our results broaden the current spectrum of known arginase inhibitors and revealed promising drug candidates for the therapy of visceral leishmaniasis.

Understanding the mechanisms of green tea EGCG against amyloid ß oligomer neurotoxicity through computational studies.

Oligomeric species of amyloid ß peptide (Aß) are pivotal in Alzheimer's disease (AD) pathogenesis, making them valuable therapeutic targets. Currently, there is no cure or preventive therapy available for AD, with only a few therapeutics offering temporary alleviation of symptoms. Natural products (NPs) are now considered promising anti-amyloid agents. Green tea catechins have garnered considerable attention due to their ability to remodel the toxic amyloid ß peptide oligomers (AßOs) into non-toxic assemblies. Nevertheless, the precise molecular mechanism underlying their effects on AßOs remains unclear. In this study, we employ a combination of binding site prediction, molecular docking, and dynamics simulations to gain mechanistic insights into the binding of the potent anti-amyloid epigallocatechin-3-gallate (EGCG) and the less effective catechin, epicatechin (EC), on the structure of pore-forming Aß tetramers (PDB ID 6RHY). This recently elucidated structure represents AßO(1-42) with two faces of the hydrophobic ß-sheet core and hydrophilic edges. Our simulations revealed three potential druggable binding sites within the AßO: two in hydrophilic edges and one in the ß-sheet core. Although both catechins bind via hydrogen bond (H-bond) and aromatic interactions to the three potential binding sites, EGCG interacted with key residues more efficiently than EC. We propose that EGCG may remodel AßOs preventing pore formation by binding to the hydrophilic edge binding sites. Additionally, EGCG interacts with key residues in the oligomer's ß-sheet core binding site, crucial for fibrillar aggregation. A better understanding of how anti-amyloid compounds remodelling AßOs could be valuable for the development of new therapeutic strategies targeting Aß in AD. Further experimental validation using point mutations involving key residues could be useful to define whether the establishment of these interactions is crucial for the EGCG remodelling effect.