Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor resulted to be the most potent one with values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl nitroalkenes are tightly binding covalent reversible inhibitors.
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Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L.
ACS Catal
May 2023
BioComp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, 12071 Castelló, Spain.
Cysteine proteases (CPs) are an important class of enzymes, many of which are responsible for several human diseases. For instance, cruzain of protozoan parasite is responsible for the Chagas disease, while the role of human cathepsin L is associated with some cancers or is a potential target for the treatment of COVID-19. However, despite paramount work carried out during the past years, the compounds that have been proposed so far show limited inhibitory action against these enzymes.
View Article and Find Full Text PDFQuantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes.
Chemistry
February 2020
Departament de Química Física i Analítica, Universitat Jaume I, 12071, Castelló, Spain.
In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz-Phe-Ala-CH=CH-NO has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The free-energy surfaces confirmed that the inhibition takes place by the formation of a covalent bond between the protein and the β-carbon atom of the inhibitor. According to the results, the tested inhibitor should be a much more efficient inhibitor of cruzain than of rhodesain, and little activity would be expected against cathepsin L, in total correspondence with the available experimental data.
View Article and Find Full Text PDFDipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain.
ACS Med Chem Lett
December 2016
Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló, Spain.
Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor resulted to be the most potent one with values of 0.49 and 0.
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