A chalcone derivative binds a putative allosteric site of YopH: Inhibition of a virulence factor of Yersinia.
Identification of allosteric inhibitors of PTPs has attracted great interest as a new strategy to overcome the challenge of discover potent and selective molecules for therapeutic intervention. YopH is a virulence factor of the genus Yersinia, validated as an antimicrobial target. The finding of a second substrate binding site in YopH has revealed a putative allosteric site that could be further exploited. Novel chalcone compounds that inhibit PTPs activity were designed and synthesized. Compound 3j was the most potent inhibitor, interestingly, with different mechanisms of inhibition for the panel of enzymes evaluated. Further, our results showed that compound 3j is an irreversible non-competitive inhibitor of YopH that binds to a site different than the catalytic site, but close to the well-known second binding site of YopH.
['de Souza|Ana C A|ACA|', 'Mori|Mattia|M|', 'Sens|Larissa|L|', 'Rocha|Ruth F|RF|', 'Tizziani|Tiago|T|', 'de Souza|Luiz F S|LFS|', 'Domeneghini Chiaradia-Delatorre|Louise|L|', 'Botta|Maurizio|M|', 'Nunes|Ricardo J|RJ|', 'Terenzi|Hernán|H|', 'Menegatti|Angela C O|ACO|']
D000495:Allosteric Site D001425:Bacterial Outer Membrane Proteins D002599:Chalcone D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D015394:Molecular Structure D017027:Protein Tyrosine Phosphatases D013329:Structure-Activity Relationship D037521:Virulence Factors
Allosteric site Yersinia PTP Non-competitive inhibitor Chicoric acid