Evidence map›Paper›PMID 40394881›Full record

ArticleAngewandte Chemie (International ed. in English)2025

Redirecting the Peptide Cleavage Causes Protease Inactivation.

Christian Breuer, Jim Küppers, Anna-Christina Schulz-Fincke, Anna Heilos, Carina Lemke, Petra Spiwoková, Janina Schmitz, Laura Cremer, Marta Frigolé-Vivas, Michael Lülsdorff and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Angewandte Chemie (International ed. in English), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Rational Engineering of AKR13B3 fromInternational journal of molecular sciences · 2026
    Article
  2. Article
  3. Redirecting the Peptide Cleavage Causes Protease Inactivation.Angewandte Chemie (International ed. in English) · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Christian Breuer *Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Jim Küppers *Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Anna-Christina Schulz-FinckePharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Anna HeilosInstitute for Physical and Theoretical Chemistry, Julius-Maximilians-Universität Würzburg, Emil-Fischer-Str. 42, 97074, Würzburg, Germany.
Carina LemkePharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.ORCID 0000-0003-4638-3396
Petra SpiwokováInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 16610, Prague, Czech Republic.ORCID 0000-0002-4734-0390
Janina SchmitzPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Laura CremerPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Marta Frigolé-VivasPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.ORCID 0000-0002-8151-5043
Michael LülsdorffPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Matthias D MertensPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Filip WichterleInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 16610, Prague, Czech Republic.ORCID 0009-0007-3293-2426
Miloš ApeltauerInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 16610, Prague, Czech Republic.ORCID 0009-0003-1489-376X
Martin HornInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 16610, Prague, Czech Republic.ORCID 0000-0001-9110-2018
Erik GilbergPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Norbert FurtmannPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Jürgen BajorathDepartment of Life Science Informatics and Data Science, B-IT, University of Bonn, Friedrich-Hirzebruch-Allee 6, 53115, Bonn, Germany.
Ulrike BartzDepartment of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, 53359, Rheinbach, Germany.
Bernd EngelsInstitute for Physical and Theoretical Chemistry, Julius-Maximilians-Universität Würzburg, Emil-Fischer-Str. 42, 97074, Würzburg, Germany.
Michael MarešInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 16610, Prague, Czech Republic.ORCID 0000-0002-0847-5022
Michael GütschowPharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.ORCID 0000-0002-9376-7897

Funding

Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, GermanyDeutsche Forschungsgemeinschaft GRK2873 (494832089)Gender Equality Center of the University of Applied Sciences Bonn-Rhein-SiegMinistry of Education, Youth, and Sports of the Czech Republic
6 · The paper itself

Abstract

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.

Indexed as

Cathepsin BPeptidesPeptidomimeticsCatalytic DomainHumansCathepsin BPeptidesPeptidomimeticsCysteine proteaseEnzyme inhibitionPeptide cleavageSuicide substratesTranscarbamoylation

Identifiers

PMID40394881
PMCPMC12304826

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.