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.
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, USA.
Kenneth
K
Knott
Jennifer
J
Fishovitz
Steven B
SB
Thorpe
Irene
I
Lee
Webster L
WL
Santos
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