▎ 摘　　要

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 x 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 x 10(-9) m) as expected with SI approximate to 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.