Targeting Protein Tyrosine Phosphatase 1B (PTP1B) to Improve Insulin Sensitivity Using Indole-Fused Glycyrrhetinic Acid Conjugates with Amino Acids

High Resolution Image Download MS PowerPoint Slide Protein Tyrosine Phosphatase 1B (PTP1B) is a crucial enzyme that significantly modulates insulin and leptin signaling, making it a highly promising target for the treatment of type 2 diabetes (T2D). We previously reported the synthesis and inhibitory activity of FC-114, an indole-fused glycyrrhetinic acid derivative that potently inhibits PTP1B. In this study, we synthesized four FC-114 conjugates with amino acids at the C30 position to enhance their inhibitory activity against PTP1B in vitro . The results indicated that incorporating glycine (compound 5a ) and serine (compound 5d ) substantially enhanced inhibitory activity against PTP1B, achieving up to 4-fold greater potency, with submicromolar IC 50 values of 0.64 and 0.54 μM, respectively. Inhibitory assessments of the short form ( h PTP1B 1-285 ) and long form ( h PTP1B 1-400 ) of PTP1B, along with enzymatic kinetics studies, molecular docking, and molecular dynamics analyses, suggested a mechanism consistent with uncompetitive inhibition, potentially involving a binding to the disordered C-terminal domain. Furthermore, both FC-114 conjugates with glycine ( 5a ) and arginine ( 5b ) significantly enhanced the mRNA expression of the GLUT4 receptor in C2C12 myoblast cells. Additionally, these compounds reduced glucose levels during the insulin tolerance test in streptozotocin-induced diabetic mice.