Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and Trypanosoma cruzi Cruzain
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Gallinamide A, originally isolated with a modest antimalarial activity, was subsequently reisolated and characterized as a potent, selective, and irreversible inhibitor of the human cysteine protease cathepsin L. Molecular docking identified potential modifications to improve binding, which were synthesized as a suite of analogs. Resultingly, this current study produced the most potent gallinamide analog yet tested against cathepsin L ( 10, K i = 0.0937 ± 0.01 nM and k inact / K i = 8 730 000). From a protein structure and substrate preference perspective, cruzain, an essential Trypanosoma cruzi cysteine protease, is highly homologous. Our investigations revealed that gallinamide and its analogs potently inhibit cruzain and are exquisitely toxic toward T. cruzi in the intracellular amastigote stage. The most active compound, 5, had an IC 50 = 5.1 ± 1.4 nM, but was relatively inactive to both the epimastigote (insect stage) and the host cell, and thus represents a new candidate for the treatment of Chagas disease.
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Cyanobacteria are a rich source of highly bioactive natural products, and in particular, protease inhibitors from numerous chemical classes.
“Cyanobacteria are known to be a rich source of highly bioactive natural products32–35, and in particular, protease inhibitors from numerous chemical classes36–41.”
From Native metabolomics identifies the rivulariapeptolide family of protease inhibitors (2022) · cites this paper as [34]
The Introduction identifies gallinamide A as a natural product isolated from marine cyanobacteria, and the Introduction and Discussion describe its potent inhibition of cysteine proteases. This supports a cyanobacterial protease inhibitor as an example, but the paper does not establish that cyanobacteria are a rich source of such products across numerous chemical classes. (LLM, conf=0.84)
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Canepa, J. I. E., Ribone, S. R., GRICH, A., Cerutti, J. P., & Quevedo, M. A. (2026) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2026.130744
Teixeira, T. R., Ryu, B., Cox, R., Deering, M., Duggan, B. M., Din, M. O., Glukhov, E., Francisco, K. R., Hu, A. J., Banh, A. H., et al. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.6c11673
Self-citationMagno, Y. C., Barbosa, L. F., de Oliveira, M. V. D., Lameira, J., & Montanari, C. A. (2026) · ChemMedChem · doi:10.1002/cmdc.70508
Highlights in Cysteine Protease Inhibitors as Antiparasitic Agents Against Trypanosomatids
Querido, B. M. R., Sousa, M. D. C., & Salvador, J. A. R. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198861
BindingDB (2021) · UC San Diego · doi:10.7270/q2pv6pqd
BindingDB (2023) · UC San Diego · doi:10.7270/q2nz8cq5
BindingDB Entry 50014331: Structure-Based Optimization of Quinazolines as Cruzain and
BindingDB (2022) · UC San Diego · doi:10.7270/q26q221r
- Authors
- Boudreau, P. D., Miller, B. W., McCall, L.-I., Almaliti, J., Reher, R., Hirata, K., Le, T., Siqueira-Neto, J. L., Hook, V., & Gerwick, W. H.
- Affiliations
- Scripps Institution of Oceanography (US)
- University of California San Diego (US)
- University of Jordan (JO)
- Corresponding author
- Gerwick, William H.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-09-20
- Volume
- 62
- Issue
- 20
- Pages
- 9026-9044
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC7240701
- OpenAlex
- W2974739675
- Cited by
- 57
- References
- 35
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 9 · 2023: 13 · 2022: 11 · 2021: 7 · 2020: 8
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (338511)
- National Institute of Neurological Disorders and Stroke (NS094597)
- National Institute of Allergy and Infectious Diseases (AI127505)
- National Institutes of Health (TW006634)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- cathepsin L, cruzain, Trypanosoma cruzi, cysteine protease inhibitors, irreversible enzyme inhibition, Chagas disease, antiparasitic drugs, molecular docking, structure-activity relationship
- MeSH terms
- Cysteine Endopeptidases, Humans, Kinetics, Trypanosoma cruzi, Drug Design, Protozoan Proteins, Cysteine Proteinase Inhibitors, Antimicrobial Cationic Peptides, Cathepsin L, Molecular Docking Simulation
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