BH3 peptide analogues are generally believed to exhibit great potency as cancer therapeutics via targeting antiapoptotic Bcl-2 proteins. Here, we describe the synthesis and identification of a new class of palmitoylated peptide BH3 analogues derived from the core region (h1–h4) of BH3 domains of proapoptotic Bcl-2 proteins and as alternative PTP1B inhibitors with antidiabetic potency in vitro and in vivo. PTP1B inhibitors are attractive for treatment of type 2 diabetes. We design the analogues using a simple lipidation approach and discovered novel lead analogues with promising antidiabetic potency in vitro and in vivo. The results presented here expanded the alternative target and function for the BH3 peptide analogues from one member Bim to other members of the proapoptotic Bcl-2 proteins and emphasize their therapeutic potential in T2DM. Furthermore, our findings may provide new proof of the regulatory function of Bcl-2 family proteins in mitochondrial nutrient and energy metabolism.

Poor medication adherence in patients with type 2 diabetes mellitus has become one of the main causes of suboptimal glycemic control. Once-weekly drugs can markedly improve the convenience, adherence, and quality of life of T2DM patients; thus, they are clinically needed and preferred. PTP1B plays a negative role in both insulin and leptin signaling pathways, which makes it an important target for diabetes. Herein, we design and synthesize 35 analogues of core BimBH3 peptide via lipidation/acylation strategy based on our previous work and evaluate their PTP1B inhibitory activity, obtaining the primary structure–activity relationship. Five compounds with good PPT1B inhibitory activity, target selectivity, and significantly improved stability were selected for molecular docking study and searching candidate molecules with long-acting antidiabetic potential. The in vivo anti-T2DM evaluation validated the once-weekly therapeutic potential of analogues 19, 26, 27, 31, and 33, which were comparable with semaglutide and therefore presented as promising drug candidates.