Convergent Protein Phosphatase Inhibitor Design for PTP1B and TCPTP: Exchangeable Vanadium Coordination Complexes on Graphene Quantum Dots

Abstract Development of potent and specific inhibitors of protein tyrosine phosphatase 1B (PTP1B) with desired drug‐like properties is still a challenge. Based on the crystal structures of PTP1B transition state analog consisting of a vanadate peptide, a novel approach is proposed to design PTP1B inhibitors, in which the tyrosyl vanadate ester of a PTP1B peptide mimic (PL1) is stably integrated on the membrane permeable graphene quantum dots (GQDs). The vanadate complexes (GQD‐PL1‐V V ) prepared exhibit high potency ( K i = 6 ± 1 × 10 −9 m ) and selectivity (selectivity index SI >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 shows selective PTP1B inhibition in liver and fat tissues and exhibits improved anti‐diabetic activity compared to bis(maltolato)oxovanadium(IV). Moreover, exchange of PL1 to a TCPTP‐specific ligand (PL2) results in potent TCPTP inhibition ( K i = 59 ± 12 × 10 −9 m ) 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.