Discovery of a new class of inhibitors for the protein arginine deiminase type 4 (PAD4) by structure-based virtual screening

<p>Abstract</p> <p>Background</p> <p>Rheumatoid arthritis (RA) is an autoimmune disease with unknown etiology. Anticitrullinated protein autoantibody has been documented as a highly specific autoantibody associated with RA. Protein arginine deiminase type 4 (PAD4) is the enzyme responsible for catalyzing the conversion of peptidylarginine into peptidylcitrulline. PAD4 is a new therapeutic target for RA treatment. In order to search for inhibitors of PAD4, structure-based virtual screening was performed using LIDAEUS (Ligand discovery at Edinburgh university). Potential inhibitors were screened experimentally by inhibition assays.</p> <p>Results</p> <p>Twenty two of the top-ranked water-soluble compounds were selected for inhibitory screening against PAD4. Three compounds showed significant inhibition of PAD4 and their IC₅₀values were investigated. The structures of the three compounds show no resemblance with previously discovered PAD4 inhibitors, nor with existing drugs for RA treatment.</p> <p>Conclusion</p> <p>Three compounds were discovered as potential inhibitors of PAD4 by virtual screening. The compounds are commercially available and can be used as scaffolds to design more potent inhibitors against PAD4.</p

Déclin de la végétation aquatique submergée au lac Saint-Pierre de 2002 à 2021

La végétation aquatique submergée (VAS) joue plusieurs rôles écologiques cruciaux et offre des services écosystémiques inestimables aux sociétés humaines. Cependant, une tendance mondiale montre un déclin de la VAS, généralement causé par la hausse des matières en suspension et des nutriments dans l’eau. L’étude de la VAS du lac Saint-Pierre de 2002 à 2021 a permis de documenter l’occurrence et la composition en espèces de cette végétation. La probabilité d’observer de la VAS aux différentes stations d’échantillonnage est passée de 75 % en 2002 à 20 % en 2021. Ce déclin de la VAS est accompagné d’un changement de composition de la communauté végétale principalement attribuable à la diminution de la vallisnérie d’Amérique (Vallisneria americana). Un potentiel refuge photique associé à la masse d’eau translucide des Grands Lacs supporterait le développement de la VAS dans le lac Saint-Pierre. Toute intervention réduisant la dispersion de cette masse d’eau dans le lac Saint-Pierre devrait être évitée. Des actions de gestion visant l’amélioration de la qualité de l’eau du lac Saint-Pierre et ses tributaires, en réduisant notamment la turbidité, sont nécessaires afin de protéger et de restaurer cette réserve mondiale de la biosphère de l’UNESCO.Submerged aquatic vegetation (SAV) plays several crucial ecological roles and provides invaluable ecosystem services to humans. However, it is declining globally, principally due to an increase in the amount of suspended matter and nutrients within water bodies. A series of studies of the SAV in Lake Saint-Pierre (Québec, Canada) conducted between 2002 and 2021, documented changes in the occurrence and species composition of this vegetation type. The probability of observing SAV at the different sampling stations decreased from 75% in 2002 to 20% in 2021. This decline was accompanied by a change in species composition, mainly associated with a decrease in the amount of American eelgrass (Vallisneria americana). The clearer mass of water flowing from the Great Lakes possibly offers a photic refuge for SAV in Lake Saint-Pierre. Any intervention that would potentially reduce the dispersion of this water mass within the lake should be avoided. Management actions aimed at improving the water quality of Lake Saint-Pierre and its tributaries, notably by reducing turbidity, are needed to restore and protect this UNESCO World Biosphere Reserve