N-Terminal peptidic boronic acids selectively inhibit human ClpXP.
The synthesis and development of N-terminal peptidic boronic acids as protease inhibitors is reported. N-Terminal peptidic boronic acids interrogate the S' sites of the target protein for selectivity and provide a new strategy that complements the currently known peptidic alpha-amino boronic acids (C-terminal boronic acids). After screening a series of N-terminal peptidic boronic acids, the first selective inhibitor of human ClpXP, an ATP-dependent serine protease present in the mitochondrial matrix, was discovered. This should facilitate the understanding of the physiological function of this protease.
Knott
Kenneth
K
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, USA.
Fishovitz
Jennifer
J
Thorpe
Steven B
SB
Lee
Irene
I
Santos
Webster L
WL
D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D049071:Endopeptidase Clp / Q000037:antagonists & inhibitors*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D001897:Boronic Acids; D010455:Peptides; D011480:Protease Inhibitors; D049071:Endopeptidase Clp