A chalcone derivative binds a putative allosteric site of YopH: Inhibition of a virulence factor of Yersinia

doi:10.1016/j.bmcl.2020.127350

Bioorganic & Medicinal Chemistry Letters

Volume 30, Issue 16, 15 August 2020, 127350

https://doi.org/10.1016/j.bmcl.2020.127350 Get rights and content

Highlights

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Novel chalcone derivatives with inhibitory activity of PTPs were synthesized.
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Compound 3j exhibited remarkable irreversible non-competitive inhibition of YopH.
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Mass spectrometry and molecular docking analysis were performed to delineate compound 3j binding interactions.

Abstract

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.

Graphical abstract

Section snippets

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We dedicate this work to the memory of Professor Maurizio Botta, a friend and mentor who loved to share knowledge. The authors would like to thank the following facilities for their contributions to this work, the Chemistry Department, Central Laboratory of Structural Biology and Clinical Analysis Laboratory Unit (Sector Microbiology, University Hospital) of the Federal University of Santa Catarina. We gratefully acknowledge financial support from CNPq and CAPES (Brazil).

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Protein phosphorylation mediated by protein kinases and phosphatases has a central regulatory function in many cellular processes in eukaryotes and prokaryotes. As a result, several diseases caused by imbalance in phosphorylation levels are known, especially due to protein tyrosine phosphatases (PTPs) activity, an important family of signaling enzymes. Furthermore, over the last decades several studies have shown the main role of PTPs in pathogenic bacteria: they are associated with growth, cell division, cell wall biosynthesis, biofilm formation, metabolic processes, as well as virulence factor. In this way, PTPs have ascended as targets for antibacterial drug design, particularly in view of the antibiotic resistance in pathogenic bacteria, which demands novel therapeutics strategies. Targeting secreted PTPs is an antivirulence strategy to combat the emergence of antimicrobial resistance (AMR). This review focuses on the recent advances in understanding the role of PTPs and the approaches to target them, with an emphasis in Yersinia spp. and Mycobacterium tuberculosis pathogenesis.
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¹: In memoriam, Professor Maurizio Botta died August 2, 2019.

View full text

A chalcone derivative binds a putative allosteric site of YopH: Inhibition of a virulence factor of Yersinia

Highlights

Abstract

Graphical abstract

Section snippets

Declaration of Competing Interest

Acknowledgments

Int J Biochem Cell Biol

Trends Pharmacol Sci

Dev Biol

J Mol Cell Cardiol

J Biol Chem

Eur J Med Chem

Eur J Med Chem

J Biol Chem

Bioorg Med Chem Lett

Bioorg Med Chem

YopH Bioorg Med Chem Lett

J Inorg Biochem

Protein tyrosine phosphatases as potential therapeutic targets

Acta Pharmacol Sin

Small molecule tools for functional interrogation of protein tyrosine phosphatases

FEBS J

Protein tyrosine phosphatase 1B inhibitors from natural sources

Arch Pharm Res

Mycobacterial Protein Tyrosine Phosphatases A and B Inhibitors Augment the Bactericidal Activity of the Standard Anti-tuberculosis Regimen

ACS Infect Dis

Drugging the Undruggable: Therapeutic Potential of Targeting Protein Tyrosine Phosphatases

Acc Chem Res

Vanadium Compounds as PTP Inhibitors

Molecules

Protein tyrosine phosphatases - from housekeeping enzymes to master regulators of signal transduction

FEBS J