Crystal structure-guided design of berberine-based novel chitinase inhibitors

Abstract

Glycoside hydrolase family 18 (GH18) chitinases play an important role in various organisms ranging from bacteria to mammals. Chitinase inhibitors have potential applications as pesticides, fungicides, and anti-asthmatics. Berberine, a plant-derived isoquinoline alkaloid, was previously reported to inhibit against various GH18 chitinases with only moderate K_i values ranging between 20 and 70 μM. In this report, we present for the first time the berberine-complexed crystal structure of SmChiB, a model GH18 chitinase from the bacterium Serratia marcescens. Based on the berberine-binding mode, a hydrophobic cavity-based optimisation strategy was developed to increase their inhibitory activity. A series of berberine derivatives were designed and synthesised, and their inhibitory activities against GH18 chitinases were evaluated. The compound 4c showed 80-fold-elevated inhibitory activity against SmChiB and the human chitinase hAMCase with K_i values at the sub-micromolar level. The mechanism of improved inhibitory activities was proposed. This work provides a new strategy for developing novel chitinase inhibitors.

Keywords:

• Berberine
• chitinase
• inhibitor
• structural optimisation

Acknowledgements

The authors thank Prof. Yong Zhou (Dalian University of Technology) for the assistance in crystal structure resolving. The authors also thank the staff of BL18U Beamline of National Facility for Protein Science Shanghai at Shanghai Synchrotron Radiation Facility for assistance during data collection.

Disclosure statement

All authors declare no competing financial interest.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [31830076, 31901916] and the Shenzhen Science and Technology Program [Grant No. KQTD20180411143628272].