Redirecting the Peptide Cleavage Causes Protease Inactivation
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Redirecting the Peptide Cleavage Causes Protease Inactivation
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Angewandte Chemie - International Edition
ISSN
1433-7851
e-ISSN
1521-3773
Volume of the periodical
64
Issue of the periodical within the volume
31
Country of publishing house
DE - GERMANY
Number of pages
5
Pages from-to
e202506832
UT code for WoS article
001522390400001
EID of the result in the Scopus database
2-s2.0-105009846562