Jingxu Li

Effect of Stapling Architecture on Physiochemical Properties and Cell Permeability of Stapled α‐Helical Peptides: A Comparative Study

Stapled peptides have emerged as a new class of targeting molecules with high binding affinity and specificity for intracellular undruggable targets. Their ability to penetrate cell membranes is exceptionally intriguing but remains elusively and controversially discussed. To understand the effect of stapling architectures on their physiochemical properties and to aid in promoting their cell permeability, we report herein a comparative study on the physiochemical properties and cell permeability of stapled α‐helical peptides with different types of crosslinks. We highlight the decisive impact of the intrinsic properties of the crosslinks on cell permeability rather than the helical contents of the peptides in model amphipathic sequences targeting estrogen receptor–coactivator interaction. We envision this finding to shed further light on the chemical optimization of stapled α‐helical peptides or macrocyclic cell‐penetrating peptides for enhanced cell penetration.

In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell

Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations. The in vivo bioactivity study of the peptide in the ovarian teratocarcinoma (PA-1) xenograft model showed a tumor growth rate inhibition of 70% with a dosage of 10 mg/kg (one injection every other day). This is the first application of a stabilized peptide modulator targeting stem-like cancer cell both in vitro and in vivo and provides references to cancer stem cell therapy.

A siRNA-induced peptide co-assembly system as a peptide-based siRNA nanocarrier for cancer therapy

Herein, we report a unique siRNA-induced peptide co-assembly nanocarrier, which could efficiently co-assemble upon the addition of siRNA, forming nanospheres with high biocompatibility and transfection efficiency both in vitro and in vivo. In a tumor xenograft nude mouse model, these siRNA–peptide nanospheres inhibited tumor volume growth by >60%.