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)

Harald Podversnik
, Shalinee Jha
, Peter Macheroux
, Rolf Breinbauer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	116831
Journal	Bioorganic and Medicinal Chemistry
Volume	67
DOIs	https://doi.org/10.1016/j.bmc.2022.116831
Publication status	Published - 1 Aug 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Bioisostere
Metalloenzyme
Peptidomimetic
Protease
Small molecule inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Fields of Expertise

Human- & Biotechnology

Cooperations

BioTechMed-Graz

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10.1016/j.bmc.2022.116831Licence: CC BY 4.0

Cite this

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title = "Design and synthesis of efficient fluororethylene-peptidomimetic inhibitors of dipeptidyl peptidase III (DPP3)",

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",

author = "Harald Podversnik and Shalinee Jha and Peter Macheroux and Rolf Breinbauer",

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year = "2022",

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doi = "10.1016/j.bmc.2022.116831",

language = "English",

volume = "67",

journal = "Bioorganic and Medicinal Chemistry",

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TY - JOUR

T1 - Design and synthesis of efficient fluororethylene-peptidomimetic inhibitors of dipeptidyl peptidase III (DPP3)

AU - Podversnik, Harald

AU - Jha, Shalinee

AU - Macheroux, Peter

AU - Breinbauer, Rolf

PY - 2022/8/1

Y1 - 2022/8/1

N2 - 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.

AB - 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.

KW - Bioisostere

KW - Metalloenzyme

KW - Peptidomimetic

KW - Protease

KW - Small molecule inhibitor

UR - https://www.scopus.com/pages/publications/85130560696

U2 - 10.1016/j.bmc.2022.116831

DO - 10.1016/j.bmc.2022.116831

M3 - Article

AN - SCOPUS:85130560696

SN - 0968-0896

VL - 67

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

M1 - 116831

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

Fields of Expertise

Cooperations

Access to Document

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