A series of our previously described BH3 peptide mimetics derived from Bim-BH3 domain core region were found to exhibit weak to potent PTP1B binding affinity and inhibitory activities via target-based drug screening. Among these compounds, a 12-aa Bim-BH3 core sequence peptide conjugated to palmitic acid (SM-6) displayed good PTP1B binding affinity (K_D = 8.38 nmol/L), inhibitory activity (IC₅₀ = 1.20 μmol/L) and selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Furthermore, SM-6 promoted HepG2 cell glucose uptake and inhibited the expression of PTP1B, indicating that SM-6 could improve the insulin resistance effect in the insulin-resistant HepG2 cell model. These results may indicate a new direction for the application of BH3 peptide mimetics and promising PTP1B peptide inhibitors could be designed and developed based on SM-6.

通过基于靶标的药物筛选，我们发现一系列先前描述的源自Bim-BH3结构域核心区域的BH3肽模拟物显示出弱至有效的PTP1B结合亲和力和抑制活性。在这些化合物中，与棕榈酸（SM-6）偶联的12-aa Bim-BH3核心序列肽表现出良好的PTP1B结合亲和力（K _D  = 8.38 nmol / L），抑制活性（IC ₅₀ = 1.20μmol/ L）和对其他PTP（TCPTP，LAR，SHP-1和SHP-2）的选择性。此外，SM-6促进HepG2细胞葡萄糖摄取并抑制PTP1B的表达，表明SM-6可以改善胰岛素抵抗性HepG2细胞模型的胰岛素抵抗作用。这些结果可能表明BH3肽模拟物的应用的新方向，可以基于SM-6设计和开发有前途的PTP1B肽抑制剂。