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Convergent Protein Phosphatase Inhibitor Design for PTP1B and TCPTP: Exchangeable Vanadium Coordination Complexes on Graphene Quantum Dots.
- Source :
-
Advanced Functional Materials . 1/26/2022, Vol. 32 Issue 5, p1-14. 14p. - Publication Year :
- 2022
-
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‐VV) prepared exhibit high potency (Ki = 6 ± 1 × 10−9m) 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‐VV 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 (Ki = 59 ± 12 × 10−9m) 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1616301X
- Volume :
- 32
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Advanced Functional Materials
- Publication Type :
- Academic Journal
- Accession number :
- 154886529
- Full Text :
- https://doi.org/10.1002/adfm.202108645