Premium
Cyanobacterial peptides as a prototype for the design of cathepsin D inhibitors
Author(s) -
Xu Hao,
Bao Keting,
Tang Shuai,
Ai Jing,
Hu Haiyan,
Zhang Wei
Publication year - 2017
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.3014
Subject(s) - chemistry , hela , amine gas treating , peptide , ic50 , moiety , cathepsin b , cathepsin d , stereochemistry , natural product , cathepsin , biochemistry , oxazole , proteases , enzyme , cell , in vitro , organic chemistry
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 IC 50 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 IC 50 of 41.8 μM. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.