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

## TL;DR

This study improves insulin sensitivity by developing new PTP1B inhibitors that show strong activity and potential for treating type 2 diabetes.

## Contribution

New indole-fused glycyrrhetinic acid conjugates with enhanced PTP1B inhibition and improved insulin sensitivity in mice.

## Key findings

- Compounds 5a and 5d showed up to 4-fold greater PTP1B inhibition with submicromolar IC50 values.
- Compounds 5a and 5b increased GLUT4 receptor mRNA expression in C2C12 myoblast cells.
- The compounds reduced glucose levels in streptozotocin-induced diabetic mice during insulin tolerance tests.

## Abstract

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 IC50 values
of 0.64 and 0.54 μM, respectively. Inhibitory assessments of
the short form (hPTP1B1‑285) and
long form (hPTP1B1‑400) 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.