Design and synthesis of efficient fluororethylene-peptidomimetic inhibitors of dipeptidyl peptidase III (DPP3)

Harald Podversnik; Shalinee Jha; Peter Macheroux; Rolf Breinbauer

doi:10.1016/j.bmc.2022.116831

Design and synthesis of efficient fluororethylene-peptidomimetic inhibitors of dipeptidyl peptidase III (DPP3)

Bioorg Med Chem. 2022 Aug 1:67:116831. doi: 10.1016/j.bmc.2022.116831. Epub 2022 May 14.

Authors

Harald Podversnik¹, Shalinee Jha², Peter Macheroux³, Rolf Breinbauer⁴

Affiliations

¹ Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
² Institute of Biochemistry, Graz University of Technology, Petersgasse 10-12, A-8010 Graz, Austria.
³ Institute of Biochemistry, Graz University of Technology, Petersgasse 10-12, A-8010 Graz, Austria; BIOTECHMED, Graz A-8010, Austria.
⁴ Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria; BIOTECHMED, Graz A-8010, Austria. Electronic address: breinbauer@tugraz.at.

PMID: 35623134
DOI: 10.1016/j.bmc.2022.116831

Abstract

Dipeptidyl peptidase III (DPP3) is a ubiquitously expressed zinc-dependent peptide cutting enzyme and selectively hydrolyses amide bonds to cleave N-terminal dipeptide fragments off of physiologically important oligopeptides. DPP3 has been found in a multitude of different types of cells and appears to be involved in various physiological processes (e.g. nociception, blood pressure control, protein turnover). Using the slowly converted peptide substrate tynorphin (VVYPW) as starting point, we have replaced the scissile bond with a fluoroethylene bioisostere to design ground state inhibitors, which led to the so far most effective peptide-based inhibitor of DPP3.

Keywords: Bioisostere; Metalloenzyme; Peptidomimetic; Protease; Small molecule inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dipeptidyl Peptidase 4
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Peptides
Peptidomimetics* / pharmacology

Substances

Peptides
Peptidomimetics
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
dipeptidyl peptidase III
Dipeptidyl Peptidase 4