System-Wide Profiling by Proteome Integral Solubility Alteration Assay of Drug Residence Times for Target Characterization
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System-Wide Profiling by Proteome Integral Solubility Alteration Assay of Drug Residence Times for Target Characterization. / Sabatier, Pierre; Beusch, Christian M.; Meng, Zhaowei; Zubarev, Roman A.
In: Analytical Chemistry, Vol. 94, No. 45, 2022, p. 15772-15780.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - System-Wide Profiling by Proteome Integral Solubility Alteration Assay of Drug Residence Times for Target Characterization
AU - Sabatier, Pierre
AU - Beusch, Christian M.
AU - Meng, Zhaowei
AU - Zubarev, Roman A.
N1 - Publisher Copyright: © 2022 American Chemical Society. All rights reserved.
PY - 2022
Y1 - 2022
N2 - Most drugs are used in the clinic and drug candidate target multiple proteins, and thus detailed characterization of their efficacy targets is required. While current methods rely on quantitative measurements at thermodynamic equilibrium, kinetic parameters such as the residence time of a drug on its target provide a better proxy for efficacy in vivo. Here, we present a residence time proteome integral solubility alteration (ResT-PISA) assay, which facilitates monitoring temporal protein solubility profiles after drug removal ("off-curve") in cell lysates or intact cells, quantifying the lifetime of drug-target interaction. A compressed version of the assay measures the integral under the off-curve enabling the multiplexing of binding affinity and residence time assessments into a single proteomic analysis. We introduce a combined scoring system for three parametric dimensions to improve prioritization of targets. By providing complementary information to other characteristics of drug-target interaction, the ResT-PISA approach will be useful in drug development and precision medicine.
AB - Most drugs are used in the clinic and drug candidate target multiple proteins, and thus detailed characterization of their efficacy targets is required. While current methods rely on quantitative measurements at thermodynamic equilibrium, kinetic parameters such as the residence time of a drug on its target provide a better proxy for efficacy in vivo. Here, we present a residence time proteome integral solubility alteration (ResT-PISA) assay, which facilitates monitoring temporal protein solubility profiles after drug removal ("off-curve") in cell lysates or intact cells, quantifying the lifetime of drug-target interaction. A compressed version of the assay measures the integral under the off-curve enabling the multiplexing of binding affinity and residence time assessments into a single proteomic analysis. We introduce a combined scoring system for three parametric dimensions to improve prioritization of targets. By providing complementary information to other characteristics of drug-target interaction, the ResT-PISA approach will be useful in drug development and precision medicine.
U2 - 10.1021/acs.analchem.2c03506
DO - 10.1021/acs.analchem.2c03506
M3 - Journal article
C2 - 36377428
AN - SCOPUS:85141680627
VL - 94
SP - 15772
EP - 15780
JO - Industrial And Engineering Chemistry Analytical Edition
JF - Industrial And Engineering Chemistry Analytical Edition
SN - 0003-2700
IS - 45
ER -
ID: 328439681