Study on the design, synthesis, and activity of anti-tumor staple peptides targeting MDM2/MDMX.

Staple peptides, which have a significantly enhanced pharmacological profile, are promising therapeutic molecules due to their remarkable resistance to proteolysis and cell-penetrating properties. In this study, we designed and synthesized a series of PMI-M3-based dual-targeting MDM2/MDMX staple peptides and compared them with straight-chain peptides. The staple peptide SM3-4 screened in the study induced apoptosis of tumor cells in vitro at low µM concentrations, and the helix was significantly increased. Studies have shown that the enhancement of staple activity is related to the increase in helicity, and SM3-4 provides an effective research basis for dual-targeted anti-tumor staple peptides.

Discovery of an orally effective double-stapled peptide for reducing ovariectomy-induced bone loss in mice.

Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells. The all-hydrocarbon peptide stapling technique has already widely adopted with great success, yielding numerous potent peptide-based molecules. Based on our prior efforts, we conceived and prepared a double-stapled peptide in this study, termed FRNC-1, which effectively attenuated the bone resorption capacity of mature osteoclasts in vitro through specific inhibition of phosphorylated GSK-3ß. The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form. Additionally, FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized (OVX) mice after intravenous injection and importantly, after oral (intragastric) administration. The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis (PMOP).

Rational design of stapled peptides targeting phosphorylated GSK3ß for regulating osteoclast differentiation.

Glycogen synthase kinase-3ß (GSK-3ß), has been reported to show essential roles in osteoclast differentiation. Modeled after FRATtide, a peptide derived from a GSK-3 binding protein, here we designed and synthesized a series of stapled peptides targeting phosphorylated GSK3ß, and evaluated the corresponding biological activities. The results indicated that stapled peptides with better helical contents and proteolytic stability than the linear ones showed improved biological activity in inhibiting osteoclast differentiation. Among them, FRC-2 and FRN-2 showed promising prospects for treating osteoporosis.