Synthesis and Structure-based Dissection of Cyclic Peptide Chitinase Inhibitors: New Leads for Antifungal and Anti-Inflammatory Drugs

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Introduction

Family 18 chitinases play key roles in the life cycles of many organisms that are pathogenic to humans, such as fungi, bacteria, and parasitic nematodes. The onset or transmission of several major human diseases (e.g. malaria, filariasis) has been linked with the activity of chitinases from such organisms, while the overexpression of endogeneous mammalian chitinases, notwithstanding the absence of chitin from mammalian physiology, is a significant feature in asthma and lipid storage disorders such as Gaucher's disease [1]. Selective inhibitors of these enzymes are of great interest as new drug leads or biochemical probes, and in this context, we recently reported the first syntheses of two cyclic peptide natural products, argifin [2] and argadin [3], that show nanomolar inhibition of a range of family 18 chitinases.

The structure of argifin in complex with various family 18 chitinases shows that the carbamoylated Arg moiety (Arg(MC)) of the cyclic peptide interacts with cons ...