Journal: iScience
Article Title: Development of a succinyl CoA:3-ketoacid CoA transferase inhibitor selective for peripheral tissues that improves glycemia in obesity
doi: 10.1016/j.isci.2025.112336
Figure Lengend Snippet: PSSI-51 selectively inhibits SCOT without interacting with canonical targets of DPBPs (A) Quantification of recombinant SCOT enzymatic activity and acetoacetyl CoA production rates in the presence of dimethyl sulfoxide (DMSO) (vehicle control) and PSSI-51 (500, 250, and 125 nmol/L) (n = 7–9 biological replicates). (B) Evaluation of C 14 βOHB oxidation rates in the isolated working mouse heart in response to vehicle control or PSSI-51 treatment (n = 5–6 animals). (C) Assessment of potential cerebral uptake of PSSI-51 and pimozide using PAMPA. (D) Fluorescence-based assay in U2OS red cAMP Nomad D2R cells to measure inhibition of dopamine-induced cAMP mobilization by PSSI-51, compared with pimozide and the positive control blenonserin ( n = 3 biological replicates). (E) Quantitative fluorescence analysis of dopamine agonistic activity ( n = 3 biological replicates). (F) Schematic of targeted site-directed mutagenesis within SCOT binding site. (G) SCOT enzymatic activity of the recombinant mutant SCOT (Y115A/I323A) and rate of acetoacetyl CoA production in the presence of DMSO (vehicle control) and the PSSI-51 (500 nmol/L) ( n = 3 technical replicates). (H) Circulating βOHB levels following PSSI-51 administration 16 h prior to oral ketone ester intake. Data are presented as mean ± SEM. Statistical significance was determined using Student’s t test or one-way ANOVA, followed by a Bonferroni post hoc correction where appropriate. Statistical thresholds set at ∗ p < 0.05 vs. vehicle control, $ p < 0.05 vs. pimozide, # p < 0.05 vs. dopamine. RMSD; root-mean-square deviation, RMSF; root-mean-square fluctuation, HP Std; high permeability standard, LP Std; low permeability standard; P e : permeability coefficients.
Article Snippet: U2OS red cAMPNomad_D2R cells (Innoprot, Spain) were maintained in DMEM/F-12 (Sigma-Aldrich D6421) supplemented with 10% FBS.
Techniques: Recombinant, Activity Assay, Control, Isolation, PAMPA Assay, Fluorescence, Inhibition, Positive Control, Mutagenesis, Binding Assay, Permeability
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