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Structure-based exploration of cyclic dipeptide chitinase inhibitors
Douglas R Houston1, Bjørnar Synstad, Vincent G H Eijsink
1Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Journal of Medicinal Chemistry
|October 29, 2004
Summary
New cyclic dipeptide derivatives effectively inhibit family 18 chitinases by mimicking reaction intermediates. The cyclo-(Gly-Pro) core allows for side-chain modifications, enabling the design of novel chitinase inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Family 18 chitinases are crucial in pathogens and pests.
- Existing inhibitors like argadin and allosamidin have known structures.
- CI-4 (cyclo-(L-Arg-D-Pro)) inhibits chitinases by mimicking reaction intermediates.
Purpose of the Study:
- To determine the high-resolution structures of four new CI-4 derivatives bound to a family 18 chitinase.
- To evaluate the enzyme inhibition and in vivo activity of these derivatives.
- To gain further insight into the mechanism of chitinase inhibition by cyclic dipeptides.
Main Methods:
- X-ray crystallography to obtain high-resolution structures.
- Enzyme inhibition assays.
- In vivo activity testing against Saccharomyces cerevisiae.
Main Results:
- Reported high-resolution structures of 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.
- Demonstrated enzyme inhibition and in vivo activity.
- Identified the cyclo-(Gly-Pro) substructure as sufficient for binding, allowing side-chain modification.
Conclusions:
- The cyclo-(Gly-Pro) core is key for binding, enabling modification for enhanced chitinase inhibition.
- Accessible chemistry allows for the design of new cyclic dipeptide inhibitors.
- These findings offer a new scaffold for developing chitinase inhibitors with potential applications against pathogens and pests.