Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin

被引:57
作者
Andersen, Ole A. [1 ]
Nathubhai, Amit [1 ]
Dixon, Mark J. [1 ]
Eggleston, Ian M. [1 ]
van Aalten, Daan M. F. [1 ]
机构
[1] Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Dundee DD1 5EH, Scotland
来源
CHEMISTRY & BIOLOGY | 2008年 / 15卷 / 03期
基金
英国生物技术与生命科学研究理事会; 英国惠康基金;
关键词
D O I
10.1016/j.chembiol.2008.02.015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides, and antiasthmatics. Argifin, a natural product cyclopentapeptide, competitively inhibits family 18 chitinases in the nanomolar to micromolar range and shows extensive substrate mimicry. In an attempt to map the active fragments of this large natural product, the cyclopentapeptide was Progressively dissected down to four linear peptides and dimethylguanylurea, synthesized using a combination of solution and solid phase peptide synthesis. The peptide fragments inhibit chitinase B1 from Aspergillus fumigatus (AfChiB1), the human chitotriosidase, and chitinase activity in lung homogenates from a murine model of chronic asthma, with potencies ranging from high nanomolar to high micromolar inhibition. X-ray crystallographic analysis of the chitinase-inhibitor complexes revealed that the conformations of the linear peptides were remarkably similar to that of the natural product. Strikingly, the dimethylguanylurea fragment, representing only a quarter of the natural product mass, was found to harbor all significant interactions with the protein and binds with unusually high efficiency. The data provide useful information that could lead to the generation of drug-like, natural product-based chitinase inhibitors.
引用
收藏
页码:295 / 301
页数:7
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