Inhibitors of cysteine proteases

Autoren

Radim Vicik
Matthias Busemann
Knut Baumann
Tanja Schirmeister

DOI

10.2174/156802606776287081

ISSN

1568-0266

Ausgabe der Veröffentlichung

4

Zeitschrift

Current Topics in Medicinal Chemistry

Sprache

en

Paginierung

331 - 353

Datum der Veröffentlichung

2006

Status

Published

Herausgeber

Bentham Science Publishers Ltd.

Herausgeber URL

http://dx.doi.org/10.2174/156802606776287081

Datum der Datenerfassung

2015

Titel

Inhibitors of Cysteine Proteases

Ausgabe der Zeitschrift

6

Datenquelle: Crossref

Abstract

The roles of cysteine proteases (CP) as protein degrading and protein processing enzymes both in physiological and pathological processes of mammals are well known. Furthermore, the key roles of CP;s in the life cycles of infectious agents like protozoa and viruses turn them into new important targets for anti-infective drugs. Thus, the effective inhibition of pathologically relevant cysteine proteases has raised increasing interest in drug development. One strategy to create CP inhibitors is the use of electrophilic moieties, which covalently bind to the cysteine residue of the active site of the target protease. In a previous approach we have selected the aziridine-2,3-dicarboxylic acid as weak electrophilic inhibitor fragment. In order to achieve effective enzyme inhibition this electrophile was incorporated into peptidic or peptidomimetic sequences addressing the substrate binding sites of the protease. High selectivity could be obtained with compounds, which bind into both the primed and non-primed substrate binding pockets. In a second approach the alpha,beta-unsaturated ketone of the well-known diuretic drug ethacrynic acid was found to be another appropriate electrophilic moiety. Derivatives thereof turned out to be new non-peptidic CP inhibitors. Results of inhibition assays obtained with these two inhibitor series on various proteases of human, protozoan, and viral origin, theoretical studies to investigate binding modes and inhibition mechanisms, and structure-activity relationships are presented. Furthermore, the results of in vitro assays on respective pathogens as well as the results of first toxicity studies are summarized.

Addresses

Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany.

Autoren

Radim Vicik
Matthias Busemann
Knut Baumann
Tanja Schirmeister

DOI

10.2174/156802606776287081

eISSN

1873-4294

Externe Identifier

PubMed Identifier: 16611146

Open access

false

ISSN

1568-0266

Ausgabe der Veröffentlichung

4

Zeitschrift

Current topics in medicinal chemistry

Schlüsselwörter

Animals
Humans
Carboxylic Acids
Fumarates
Epoxy Compounds
Sulfones
Aziridines
Cysteine Proteinase Inhibitors
Models, Molecular

Sprache

eng

Medium

Print

Paginierung

331 - 353

Datum der Veröffentlichung

2006

Status

Published

Datum der Datenerfassung

2006

Titel

Inhibitors of cysteine proteases.

Sub types

Review
Journal Article

Ausgabe der Zeitschrift

6

Datenquelle: Europe PubMed Central

Abstract

The roles of cysteine proteases (CP) as protein degrading and protein processing enzymes both in physiological and pathological processes of mammals are well known. Furthermore, the key roles of CP;s in the life cycles of infectious agents like protozoa and viruses turn them into new important targets for anti-infective drugs. Thus, the effective inhibition of pathologically relevant cysteine proteases has raised increasing interest in drug development. One strategy to create CP inhibitors is the use of electrophilic moieties, which covalently bind to the cysteine residue of the active site of the target protease. In a previous approach we have selected the aziridine-2,3-dicarboxylic acid as weak electrophilic inhibitor fragment. In order to achieve effective enzyme inhibition this electrophile was incorporated into peptidic or peptidomimetic sequences addressing the substrate binding sites of the protease. High selectivity could be obtained with compounds, which bind into both the primed and non-primed substrate binding pockets. In a second approach the alpha,beta-unsaturated ketone of the well-known diuretic drug ethacrynic acid was found to be another appropriate electrophilic moiety. Derivatives thereof turned out to be new non-peptidic CP inhibitors. Results of inhibition assays obtained with these two inhibitor series on various proteases of human, protozoan, and viral origin, theoretical studies to investigate binding modes and inhibition mechanisms, and structure-activity relationships are presented. Furthermore, the results of in vitro assays on respective pathogens as well as the results of first toxicity studies are summarized.

Autoren

Radim Vicik
Matthias Busemann
Knut Baumann
Tanja Schirmeister

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/16611146

DOI

10.2174/156802606776287081

ISSN

1568-0266

Ausgabe der Veröffentlichung

4

Zeitschrift

Curr Top Med Chem

Schlüsselwörter

Animals
Aziridines
Carboxylic Acids
Cysteine Proteinase Inhibitors
Epoxy Compounds
Fumarates
Humans
Models, Molecular
Sulfones

Sprache

eng

Country

United Arab Emirates

Paginierung

331 - 353

Datum der Veröffentlichung

2006

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2006

Titel

Inhibitors of cysteine proteases.

Sub types

Journal Article
Review

Ausgabe der Zeitschrift

6

Datenquelle: PubMed

Werkzeuge