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Structure-based exploration of cyclic dipeptide chitinase inhibitors.

Abstract：

:Family 18 chitinases play an essential role in a range of pathogens and pests. Several inhibitors are known, including the potent inhibitors argadin and allosamidin, and the structures of these in complex with chitinases have been elucidated. Recent structural analysis has revealed that CI-4 [cyclo-(L-Arg-D-Pro)] inhibits family 18 chitinases by mimicking the structure of the proposed reaction intermediate. Here we report the high-resolution structures of four new CI-4 derivatives, cyclo-(L-Arg-L-Pro), cyclo-(Gly-L-Pro), cyclo-(L-His-L-Pro), and cyclo-(L-Tyr-L-Pro), in complex with a family 18 chitinase. In addition, details of enzyme inhibition and in vivo activity against Saccharomyces cerevisiae are presented. The structures reveal that the common cyclo-(Gly-Pro) substructure is sufficient for binding, allowing modification of the side chain of the nonproline residue. This suggests that design of cyclic dipeptides with a view to increasing inhibition of family 18 chitinases should be possible through relatively accessible chemistry. The derivatives presented here in complex with chitinase B from Serratia marcescens provide further insight into the mechanism of inhibition of chitinases by cyclic dipeptides as well as providing a new scaffold for chitinase inhibitor design.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Houston DR,Synstad B,Eijsink VG,Stark MJ,Eggleston IM,van Aalten DM

doi

10.1021/jm049940a

keywords:

subject

Has Abstract

pub_date

2004-11-04 00:00:00

pages

5713-20

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

47

pub_type

杂志文章

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