Redirecting the Peptide Cleavage Causes Protease Inactivation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00637741" target="_blank" >RIV/61388963:_____/25:00637741 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1002/anie.202506832" target="_blank" >https://doi.org/10.1002/anie.202506832</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/anie.202506832" target="_blank" >10.1002/anie.202506832</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Redirecting the Peptide Cleavage Causes Protease Inactivation

Popis výsledku v původním jazyce

Cysteine and serine proteases cleave peptides through covalent catalysis by generating a transient adduct with the N-terminal part of the substrate after releasing its C-terminal part. We demonstrate the unique redirection of this event leading to strong enzyme inactivation. For targeting human cathepsin B, a cysteine protease of significant therapeutic importance, we designed tailored peptidomimetics with a variety of dipeptide fragments directed toward the occluding loop and equipped with numerous N-terminal carbamate warheads. The carbamate deprotonation catalyzed by the active site thiolate initiates the redirected cleavage. The C-terminal part of the inhibitors remains covalently attached to the protease. Hydrolysis of such carbamoyl-enzyme complexes is catalytically unsupported rendering inhibition irreversible. This novel mechanism of action comprises a significant extension of the covalent drug space.

Název v anglickém jazyce

Redirecting the Peptide Cleavage Causes Protease Inactivation

Popis výsledku anglicky

Cysteine and serine proteases cleave peptides through covalent catalysis by generating a transient adduct with the N-terminal part of the substrate after releasing its C-terminal part. We demonstrate the unique redirection of this event leading to strong enzyme inactivation. For targeting human cathepsin B, a cysteine protease of significant therapeutic importance, we designed tailored peptidomimetics with a variety of dipeptide fragments directed toward the occluding loop and equipped with numerous N-terminal carbamate warheads. The carbamate deprotonation catalyzed by the active site thiolate initiates the redirected cleavage. The C-terminal part of the inhibitors remains covalently attached to the protease. Hydrolysis of such carbamoyl-enzyme complexes is catalytically unsupported rendering inhibition irreversible. This novel mechanism of action comprises a significant extension of the covalent drug space.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Angewandte Chemie - International Edition

ISSN

1433-7851

e-ISSN

1521-3773

Svazek periodika

64

Číslo periodika v rámci svazku

31

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

5

Strana od-do

e202506832

Kód UT WoS článku

001522390400001

EID výsledku v databázi Scopus

2-s2.0-105009846562