Protein tyrosine phosphatases are critical enzymes involved in signal transduction and vanadate and vanadium compounds comprise a potent group of inhibitors. In the following work we describe development of a potent and specific inhibitor of protein tyrosine phosphatase 1B (PTP1B) with desired drug-like properties. Based on the crystal structures of PTP1B transition state analog consisting of a vanadate peptide, we proposed a novel approach to design PTP1B inhibitors, in which the tyrosyl vanadate ester of a PTP1B peptide mimic (PL1) was stably integrated on the membrane permeable graphene quantum dots (GQDs). The vanadate complexes (GQD-PL1-V(V)) prepared exhibited high potency (Ki = 6 ± 1 nM) and selectivity (selectivity index SI &gt;200 for PTP1B versus the T-cell protein tyrosine phosphatase, TCPTP) in solution and in HepG2 cells. Oral administration of GQD-PL1-V(V) in db/db model mice showed selective PTP1B inhibition in liver and fat tissues and exhibited improved anti-diabetic activity compared to bis(maltolato)oxovanadium(IV). Moreover, exchange of PL1 to a TCPTP-specific ligand (PL2) resulted in potent TCPTP inhibition (Ki = 59 ± 12 nM) as expected with SI ~23 versus PTP1B. Overall, the present results provide a paradigm shift and a general design of phosphatase inhibitors consisting of GQDs, a complexing targeting ligand and vanadium(V) for selective regulation of PTP1B both in vitro and vivo.

Convergent protein phosphatase inhibitor design for PTP1B and TCPTP: Exchangeable vanadium coordination complexes on graphene quantum dots

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.