Target identification using drug affinity responsive target stability (DARTS).
Identifying the molecular targets for the beneficial or detrimental effects of small-molecule drugs is an important and currently unmet challenge. We have developed a method, drug affinity responsive target stability (DARTS), which takes advantage of a reduction in the protease susceptibility of the target protein upon drug binding. DARTS is universally applicable because it requires no modification of the drug and is independent of the mechanism of drug action. We demonstrate use of DARTS to identify known small-molecule-protein interactions and to reveal the eukaryotic translation initiation machinery as a molecular target for the longevity-enhancing plant natural product resveratrol. We envisage that DARTS will also be useful in global mapping of protein-metabolite interaction networks and in label-free screening of unlimited varieties of compounds for development as molecular imaging agents.
Lomenick
Brett
B
Department of Molecular and Medical Pharmacology and the Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Hao
Rui
R
Jonai
Nao
N
Chin
Randall M
RM
Aghajan
Mariam
M
Warburton
Sarah
S
Wang
Jianing
J
Wu
Raymond P
RP
Gomez
Fernando
F
Loo
Joseph A
JA
Wohlschlegel
James A
JA
Vondriska
Thomas M
TM
Pelletier
Jerry
J
Herschman
Harvey R
HR
Clardy
Jon
J
Clarke
Catherine F
CF
Huang
Jing
J
D001665:Binding Sites; D018076:DNA, Complementary; D016503:Drug Delivery Systems; D040901:Proteomics; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism
D018076:DNA, Complementary; D013267:Stilbenes; D000077185:Resveratrol