Evidence map›Paper›PMID 40346252›Full record

ArticleNature chemical biology2025

Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors.

Mengting Liu, Xin Zang, Niko W Vlahakis, Jose A Rodriguez, Masao Ohashi, Yi Tang

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. Catalytically Active Recombinant Cysteine Proteases ofInternational journal of molecular sciences · 2025
    Article
  2. Review
  3. Combining MicroED and native mass spectrometry for structural discovery of enzyme-small molecule complexes.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  4. 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

6 authors.

Mengting LiuDepartment of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
Xin ZangDepartment of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
Niko W VlahakisDepartment of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, Los Angeles, Los Angeles, CA, USA.
Jose A RodriguezDepartment of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, Los Angeles, Los Angeles, CA, USA.
Masao OhashiDepartment of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA. gph422001@ucla.edu.ORCID http://orcid.org/0000-0001-7103-541X
Yi TangDepartment of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA. yitang@ucla.edu.ORCID http://orcid.org/0000-0003-1597-0141

Funding

Howard Hughes Medical Institute (HHMI) the Emerging Pathogen Initiative
6 · The paper itself

Abstract

E-64 is an irreversible cysteine protease inhibitor prominently used in chemical biology and drug discovery. Here we uncover a nonribosomal peptide synthetase-independent biosynthetic pathway for E-64, which is widely conserved in fungi. The pathway starts with epoxidation of fumaric acid to the warhead (2S,3S)-trans-epoxysuccinic acid with an Fe(II)/α-ketoglutarate-dependent oxygenase, followed by successive condensation with an L-amino acid by an adenosine triphosphate grasp enzyme and with an amine by the fungal example of amide bond synthetase. Both amide bond-forming enzymes display notable biocatalytic potential, including scalability, stereoselectivity toward the warhead and broader substrate scopes in forming the amide bonds. Biocatalytic cascade with these amide bond-forming enzymes generated a library of cysteine protease inhibitors, leading to more potent cathepsin inhibitors. Additionally, one-pot reactions enabled the preparative synthesis of clinically relevant inhibitors. Our work highlights the importance of biosynthetic investigation for enzyme discovery and the potential of amide bond-forming enzymes in synthesizing small-molecule libraries.

Indexed as

Combinatorial Chemistry TechniquesCysteine Proteinase InhibitorsBiocatalysisLeucinePeptide SynthasesCysteine Proteinase InhibitorsLeucinePeptide Synthasesubenimex

Identifiers

PMID40346252
PMCPMC12568646

What OpenQuestion holds

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LicenceCC BY
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Registered trials

None linked

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.