New peptidic cysteine protease inhibitors derived from the electrophilic α-amino acid aziridine-2,3-dicarboxylic acid

Autoren

Tanja Schirmeister

DOI

10.1021/jm981061z

eISSN

1520-4804

ISSN

0022-2623

Ausgabe der Veröffentlichung

4

Zeitschrift

Journal of Medicinal Chemistry

Sprache

en

Online publication date

1999

Paginierung

560 - 572

Datum der Veröffentlichung

1999

Status

Published

Herausgeber

American Chemical Society (ACS)

Herausgeber URL

http://dx.doi.org/10.1021/jm981061z

Datum der Datenerfassung

2021

Titel

New Peptidic Cysteine Protease Inhibitors Derived from the Electrophilic α-Amino Acid Aziridine-2,3-dicarboxylic Acid

Ausgabe der Zeitschrift

42

Data source: Crossref

Abstract

Three different types of peptides containing aziridine-2, 3-dicarboxylic acid (Azi) as an electrophilic alpha-amino acid at different positions within the peptide chain (type I, N-acylated aziridines with Azi as C-terminal amino acid; type II, N-unsubstituted aziridines with Azi as N-terminal amino acid; type III, N-acylated bispeptidyl derivatives of Azi) have been synthesized and tested as inhibitors of the cysteine proteases papain, cathepsins B, L, and H, and calpains I and II, as well as against several serine proteases, one aspartate, and one metalloprotease. All aziridinyl peptides are specific cysteine protease inhibitors. Papain and cathepsins B and L are inhibited irreversibly, whereas cathepsin H and calpains are inhibited in a non-time-dependent manner. Some compounds turned out to be substrates for serine proteases and for the metalloprotease thermolysin. Remarkable differences can be observed between the three different types of inhibitors concerning stereospecificity, pH dependency of inhibition, selectivity between different cysteine proteases, and the importance of a free carboxylic acid function at the aziridine ring for inhibition. Above all type II inhibitors, aza analogues of the well-known epoxysuccinyl peptides, are potent cysteine protease inhibitors. With the exception of BOC-Leu-Gly-(S, S+R,R)-Azi-(OEt)2 (28a+b), a highly selective and potent cathepsin L inhibitor, N-acylated aziridines of type I are weaker inhibitors than type II or type III compounds. The observed results can be explained by different binding modes of the three types of inhibitors with respect to their orientation in the S- and S'-binding sites of the enzymes. Furthermore, the presence of a protonated aziridine N modifies the binding mode of type II inhibitors.

Addresses

Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Albert-Ludwigs-University of Freiburg, Hermann-Herder-Strasse 9, D-79104 Freiburg, Germany.

Autoren

T Schirmeister

DOI

10.1021/jm981061z

eISSN

1520-4804

Externe Identifier

PubMed Identifier: 10052963

Open access

false

ISSN

0022-2623

Ausgabe der Veröffentlichung

4

Zeitschrift

Journal of medicinal chemistry

Schlüsselwörter

Aziridines
Endopeptidases
Cathepsins
Cathepsin B
Cysteine Endopeptidases
Papain
Peptides
Cysteine Proteinase Inhibitors
Protein Conformation
Structure-Activity Relationship
Kinetics
Stereoisomerism
Hydrogen-Ion Concentration
Models, Molecular
Cathepsin L

Sprache

eng

Medium

Print

Paginierung

560 - 572

Datum der Veröffentlichung

1999

Status

Published

Datum der Datenerfassung

1999

Titel

New peptidic cysteine protease inhibitors derived from the electrophilic alpha-amino acid aziridine-2,3-dicarboxylic acid.

Sub types

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

Ausgabe der Zeitschrift

42

Data source: Europe PubMed Central

Abstract

Three different types of peptides containing aziridine-2, 3-dicarboxylic acid (Azi) as an electrophilic alpha-amino acid at different positions within the peptide chain (type I, N-acylated aziridines with Azi as C-terminal amino acid; type II, N-unsubstituted aziridines with Azi as N-terminal amino acid; type III, N-acylated bispeptidyl derivatives of Azi) have been synthesized and tested as inhibitors of the cysteine proteases papain, cathepsins B, L, and H, and calpains I and II, as well as against several serine proteases, one aspartate, and one metalloprotease. All aziridinyl peptides are specific cysteine protease inhibitors. Papain and cathepsins B and L are inhibited irreversibly, whereas cathepsin H and calpains are inhibited in a non-time-dependent manner. Some compounds turned out to be substrates for serine proteases and for the metalloprotease thermolysin. Remarkable differences can be observed between the three different types of inhibitors concerning stereospecificity, pH dependency of inhibition, selectivity between different cysteine proteases, and the importance of a free carboxylic acid function at the aziridine ring for inhibition. Above all type II inhibitors, aza analogues of the well-known epoxysuccinyl peptides, are potent cysteine protease inhibitors. With the exception of BOC-Leu-Gly-(S, S+R,R)-Azi-(OEt)2 (28a+b), a highly selective and potent cathepsin L inhibitor, N-acylated aziridines of type I are weaker inhibitors than type II or type III compounds. The observed results can be explained by different binding modes of the three types of inhibitors with respect to their orientation in the S- and S'-binding sites of the enzymes. Furthermore, the presence of a protonated aziridine N modifies the binding mode of type II inhibitors.

Autoren

T Schirmeister

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/10052963

DOI

10.1021/jm981061z

ISSN

0022-2623

Ausgabe der Veröffentlichung

4

Zeitschrift

J Med Chem

Schlüsselwörter

Aziridines
Cathepsin B
Cathepsin L
Cathepsins
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors
Endopeptidases
Hydrogen-Ion Concentration
Kinetics
Models, Molecular
Papain
Peptides
Protein Conformation
Stereoisomerism
Structure-Activity Relationship

Sprache

eng

Country

United States

Paginierung

560 - 572

PII

jm981061z

Datum der Veröffentlichung

1999

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

1999

Titel

New peptidic cysteine protease inhibitors derived from the electrophilic alpha-amino acid aziridine-2,3-dicarboxylic acid.

Sub types

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

Ausgabe der Zeitschrift

42

Data source: PubMed

New peptidic cysteine protease inhibitors derived from the electrophilic α-amino acid aziridine-2,3-dicarboxylic acid

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