Restricted Research - Award List, Note/Discussion Page
Fiscal Year: 2023
2382 The University of Texas at San Antonio (144270)
Principal Investigator: Liu, Aimin
Total Amount of Contract, Award, or Gift (Annual before 2011): $ 174,302
Exceeds $250,000 (Is it flagged?): No
Start and End Dates: 7/1/22 - 6/30/24
Restricted Research: YES
Academic Discipline: SCIENCES
Department, Center, School, or Institute: Cos Chemistry
Title of Contract, Award, or Gift: Identification of CNS-Penetrant TDO Degrading Liga
Name of Granting or Contracting Agency/Entity:
Purdue University
CFDA Link: HHS
93.866
Program Title:
none
CFDA Linked: Aging Research
Note:
SAMs 1.1.1; In this research project, the UTSA team will lead biochemical characterization studies according to the following plan, 1) analyze the roles of key amino acids at the degradation signaling site by generating mutant hTDO proteins and studying protein secondary structure (circular dichroism), stability (differential scanning calorimetry), and binding affinity of known ligands (isothermal titration calorimetry), 2) for roughly 200 analogs identified from the virtual screen and synthesized Trp analogs, the UTSA team will evaluate the ability of ligands to stimulate hTDO degradation. The assays will be the first run at 1 mM, and reconfirmation will occur at 10 μM. Analogs promoting degradation over 20% at both concentrations will then be subjected to an 8-point dose-response to determine IC50 values, 3) Based on results from the previous assays, the UTSA team will perform inhibition studies of 5 analogs to determine whether analogs inhibit TDO catalytic activity, and 4) Based on results from the previous assays, the Liu team will measure the binding affinities of 5 top-performing analogs to hTDO (and M108I, control) using ITC and spectroscopic methods.
Discussion: No discussion notes