Creation of CustomizedBioactivity within a 14-MemberedMacrolide Scaffold: Design, Synthesis, and Biological Evaluation Usinga Family-18 Chitinase.

Argifin,a 17-membered pentapeptide, inhibits chitinase. As argifinhas properties that render it unsuitable as a drug development candidate,we devised a mechanism to create the structural component of argifinthat bestows the chitinase inhibition and introduce it into a 14-memberedmacrolide scaffold. Here we describe (1) the designed macrolide, whichexhibits ∼200-fold more potent chitinase inhibition than argifin,(2) the binding modes of the macrolide with Serratia marcescenschitinase B, and (3) the computed analysis explaining the reasonfor derivatives displaying increased inhibition compared to argifin,the macrolide aglycone displaying inhibition in a nanomolar range.This promises a class of chitinase inhibitors with novel skeletons,providing innovative insight for drug design and the use of macrolidesas adaptable, flexible templates for use in drug discovery researchand development. [ABSTRACT FROM AUTHOR]