The development of selective inhibitors for ER α-mannosidase I by combinatorial modification of kifunensine and deoxymannojirimycin

Abstract

Selective inhibitors of endoplasmic reticulum -mannosidase I (ER Man I) have the potential to be used for treatment of a number of genetic diseases. Although potent inhibitors for this enzyme have been described, in general these compounds display poor selectivity and often inhibit Golgi -mannosidase I. To address this difficulty, we have synthesized and combinatorial modified kifunensine, which is a potent GH47 -mannosidase I inhibitor, and 1-deoxymannojirimycin, a weak -mannosidase I inhibitor. Kifunensine was modified by a hydrazone moiety, which could easily be extended by reaction with a range of aldehydes. The library of hydrazone-linked analogues was screened for inhibition of human ER Man I and mouse Golgi Man I. It was found that a pyridine functionalized kifunensine analog selectively inhibited ER Man I. Based on this finding, a second generation of analogues was prepared in which a functionalized pyridine scaffold was coupled to kifunensine through the hydrazone moiety. 1-Deoxymannojirimycin was modified by a hydrazine moiety, which could easily be extended by reaction with a range of aldehydes. The library of hydrazone-linked DMJ analogues was screened for inhibition of human ER Man I and mouse Golgi Man I.