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Cyanobacterial peptides as a prototype for the design of cathepsin D inhibitors
Hao Xu1, Keting Bao2, Shuai Tang3
1Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, 316022, China.
Abstract:
Cathepsin D (Cath D) is overexpressed and secreted in a number of solid tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis. Inhibition of Cath D is regarded as an attractive pathway for the development of novel anticancer drugs. Our previous studies revealed that tasiamide B, a cyanobacterial peptide that contained a statine-like unit, exhibited good inhibition against Cath D and other aspartic proteases. Using this natural product as prototype, we designed and synthesized three new analogs, which bear isophthalic acid fragment at the N-terminus and isobutyl amine (1), cyclopropyl amine (2), or 3-methoxybenzyl amine (3) moiety at the C-terminus. Enzymatic assays revealed that all these three compounds showed moderate-to-good inhibition against Cath D, with IC50 s of 15, 884, and 353 nM, respectively. Notably, compound 1 showed extreme selectivity for Cath D with 576-fold over Cath E and 554-fold over BACE1, which could be a valuable template for the design of highly potent and selective Cath D inhibitors. Additionally, compound 1 showed moderated activity against HeLa cell lines with IC50 of 41.8 μM. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Insights
New analogs of tasiamide B were synthesized to inhibit Cathepsin D (Cath D), a key protein in tumor progression. Compound 1 demonstrated potent and selective Cath D inhibition, offering a template for novel anticancer drug development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Cathepsin D (Cath D) is overexpressed in solid tumors, promoting invasion, proliferation, metastasis, and apoptosis.
- Inhibiting Cath D is a promising strategy for developing new anticancer drugs.
- Tasiamide B, a natural peptide, showed prior inhibition of Cath D and other aspartic proteases.
Purpose of the Study:
- To design and synthesize novel analogs of tasiamide B.
- To evaluate the inhibitory activity and selectivity of these analogs against Cathepsin D.
- To explore potential anticancer applications.
Main Methods:
- Chemical synthesis of three tasiamide B analogs with modifications at the N- and C-termini.
- Enzymatic assays to determine inhibition constants (IC50) against Cath D.
- Selectivity profiling against related proteases (Cath E, BACE1).
- Cell-based assays using HeLa cell lines.
Main Results:
- All three synthesized compounds exhibited moderate-to-good inhibition against Cath D.
- Compound 1 displayed potent inhibition (IC50 = 15 nM) and high selectivity for Cath D over Cath E and BACE1.
- Compound 1 showed moderate activity against HeLa cancer cells (IC50 = 41.8 μM).
Conclusions:
- The designed tasiamide B analogs are effective inhibitors of Cathepsin D.
- Compound 1 represents a highly potent and selective Cath D inhibitor template for anticancer drug discovery.
- Further investigation of compound 1 is warranted for its therapeutic potential.
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