Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases-Studies on Inhibition Mechanism and Kinetics

Abstract

The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.

Autoren

Philipp Klein
Fabian Barthels
Patrick Johe
Annika Wagner
Stefan Tenzer
Ute Distler
Thien Anh Le
Paul Schmid
Volker Engel
Bernd Engels
Ute A Hellmich
Till Opatz
Tanja Schirmeister

DOI

10.3390/molecules25092064

eISSN

1420-3049

Ausgabe der Veröffentlichung

9

Zeitschrift

Molecules

Sprache

en

Online publication date

2020

Paginierung

2064 - 2064

Status

Published online

Herausgeber

MDPI AG

Herausgeber URL

http://dx.doi.org/10.3390/molecules25092064

Datum der Datenerfassung

2020

Titel

Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases—Studies on Inhibition Mechanism and Kinetics

Ausgabe der Zeitschrift

25

Datenquelle: Crossref

Abstract

The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.

Addresses

Department of Chemistry, Organic Chemistry Section, Johannes Gutenberg-Universität, Duesbergweg 10-14, 55128 Mainz, Germany.

Autoren

Philipp Klein
Fabian Barthels
Patrick Johe
Annika Wagner
Stefan Tenzer
Ute Distler
Thien Anh Le
Paul Schmid
Volker Engel
Bernd Engels
Ute A Hellmich
Till Opatz
Tanja Schirmeister

DOI

10.3390/molecules25092064

eISSN

1420-3049

Externe Identifier

PubMed Identifier: 32354191
PubMed Central ID: PMC7248907

Funding acknowledgements

Center for Biomolecular Magnetic Resonance: University of Frankfurt
Carl-Zeiss Foundation: ChemBioMed

Open access

true

ISSN

1420-3049

Ausgabe der Veröffentlichung

9

Zeitschrift

Molecules (Basel, Switzerland)

Schlüsselwörter

Trypanosoma brucei brucei
Esters
Naphthoquinones
Cysteine Endopeptidases
Dipeptides
Prodrugs
Cysteine Proteinase Inhibitors
Trypanocidal Agents
Inhibitory Concentration 50
Structure-Activity Relationship
Hydrolysis
Kinetics
Electrons
Quantum Theory
Mass Spectrometry
Cathepsin L
Cysteine Proteases

Sprache

eng

Medium

Electronic

Online publication date

2020

Open access status

Open Access

Paginierung

E2064

Datum der Veröffentlichung

2020

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2020

Titel

Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases-Studies on Inhibition Mechanism and Kinetics.

Sub types

research-article
Journal Article

Ausgabe der Zeitschrift

25

Files

https://www.mdpi.com/1420-3049/25/9/2064/pdf?version=1588339458 https://europepmc.org/articles/PMC7248907?pdf=render

Datenquelle: Europe PubMed Central

Abstract

The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.

Date of acceptance

2020

Autoren

Philipp Klein
Fabian Barthels
Patrick Johe
Annika Wagner
Stefan Tenzer
Ute Distler
Thien Anh Le
Paul Schmid
Volker Engel
Bernd Engels
Ute A Hellmich
Till Opatz
Tanja Schirmeister

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/32354191

DOI

10.3390/molecules25092064

eISSN

1420-3049

Externe Identifier

PubMed Central ID: PMC7248907

Funding acknowledgements

Carl-Zeiss Foundation: ChemBioMed
Center for Biomolecular Magnetic Resonance: University of Frankfurt

Ausgabe der Veröffentlichung

9

Zeitschrift

Molecules

Schlüsselwörter

1,4-naphthoquinone
covalent reversible inhibition
nucleophilic addition
prodrug
protease
rhodesain
Cathepsin L
Cysteine Endopeptidases
Cysteine Proteases
Cysteine Proteinase Inhibitors
Dipeptides
Electrons
Esters
Hydrolysis
Inhibitory Concentration 50
Kinetics
Mass Spectrometry
Naphthoquinones
Prodrugs
Quantum Theory
Structure-Activity Relationship
Trypanocidal Agents
Trypanosoma brucei brucei

Sprache

eng

Country

Switzerland

PII

molecules25092064

Datum der Veröffentlichung

2020

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2021

Titel

Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases-Studies on Inhibition Mechanism and Kinetics.

Sub types

Journal Article

Ausgabe der Zeitschrift

25

Datenquelle: PubMed

Author's licence

CC-BY

Autoren

Philipp Klein
Fabian Barthels
Patrick Johe
Annika Wagner
Stefan Tenzer
Ute Distler
Thien Anh Le
Paul Schmid
Volker Engel
Bernd Engels
Ute Hellmich
Till Opatz
Tanja Schirmeister

Hosting institution

Universitätsbibliothek Mainz

Sammlungen

JGU-Publikationen

Resource version

Published version

DOI

10.3390/molecules25092064

Funding acknowledgements

DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin

File(s) embargoed

false

Open access

true

ISSN

1420-3049

Ausgabe der Veröffentlichung

9

Zeitschrift

Molecules

Schlüsselwörter

570 Biowissenschaften
570 Life sciences

Sprache

eng

Open access status

Open Access

Paginierung

Art. 2064

Datum der Veröffentlichung

2020

Public URL

https://openscience.ub.uni-mainz.de/handle/20.500.12030/414

Herausgeber

MDPI

Herausgeber URL

http://dx.doi.org/10.3390/molecules25092064

Datum der Datenerfassung

2020

Datum, an dem der Datensatz öffentlich gemacht wurde

2020

Zugang

Public

Titel

Naphthoquinones as covalent reversible inhibitors of cysteine proteases : studies on inhibition mechanism and kinetics

Ausgabe der Zeitschrift

25

Files

59874.pdf

Datenquelle: OPENSCIENCE.UB

Naphthoquinones as Covalent Reversible Inhibitors of Cysteine Proteases-Studies on Inhibition Mechanism and Kinetics

Files

Files

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