Radiation therapy is one of the most common treatments for cancer. However, enhancing tumors' radiation sensitivity and overcoming tolerance remain a challenge. Previous studies have shown that the Ras signaling pathway directly influences tumor radiation sensitivity. Herein, we designed a series of Ras-targeting stabilized peptides, with satisfactory binding affinity (KD = 0.13 μM with HRas) and good cellular uptake. Peptide H5 inhibited downstream phosphorylation of ERK and increased radio-sensitivity in HeLa cells, resulting in significantly reduced clonogenic survival. The stabilized peptides, designed with an N-terminal nucleation strategy, acted as potential radio-sensitizers and broadened the applications of this kind of molecule. This is the first report of using stabilized peptides as radio-sensitizers, broadening the applications of this kind of molecule.

A chirality induced helicity method has been developed to modulate the peptide’s biophysical and biochemical properties. We report herein a novel approach for reversibly switching the conformation of short constraint α-helical peptides through alkylation of the in-tether thioether and dealkylation of the chiral sulfonium. This traceless redox sensitive tagging strategy broadened our scope of CIH (chirality induced helicity) strategy and provided a valuable approach to functionalize the peptide tether.

Insulin-degrading enzyme (IDE) plays a critical role in both the proteolytic degradation and inactivation of insulin. The exploration of novel IDE inhibitors could aid in the study of novel therapeutics for type-2 diabetes. Herein, we report a hypothesized stabilized β-hairpin peptide that can efficiently inhibit the enzymatic activity of IDE. The resulting stabilized peptide B35 is demonstrated to activate the AKT phosphorylation pathway in skeletal muscle cells and is shown to slow insulin degradation. An 80 mg kg-1 intraperitoneal (i.p.) injection of the stabilized β-hairpin peptide B35 is demonstrated to improve glucose tolerance during an oral glucose tolerance test in obese mouse model. We note that this stabilized peptide exhibited negligible cytotoxicity in both in vitro and in vivo assays, even at high concentrations (300 μM). This study suggests that IDE peptide inhibitors could function as potentially meaningful candidates for the development of type-2 diabetes therapeutics.

Conformationally constrained peptides with either α-helical or β-hairpin conformations, possessing different topological distribution of hydrophobic and hydrophilic residues, displayed distinct anti-microbial activity towards Gram positive and Gram negative bacteria and fungi.

Cell penetration and nucleus translocation efficiency are important for the cellular activities of peptide therapeutics. For helical peptides stabilized by N-terminal crosslinked aspartic acid, correlations between their penetration efficiency/nucleus translocation and physicochemical properties were studied. An increase in hydrophobicity and isoelectric point will promote cellular uptake and nucleus translocation of stabilized helices.

A fluorescent dye, FEB, with high fluorescence quantum yield for tumour imaging is reported. FEB dyes can be efficiently synthesized in three steps and then easily modified with either PEG or PEG-iRGD to yield FEB2000 or FEB-2000-iRGD, respectively. Bothmodified dyes showed negligible toxicity and were thus able to be adopted for in vivo tumour imaging. PEG modification endowed the dye FEB-2000 with both long circulating times and good tumour targeting properties in a MDA-MB-231 xenograft model. Further conjugation with iRGD to generate FEB-2000-iRGD showed minimal targeting enhancement. These results provide a template for the efficient preparation of FEB dyes for use in tumour imaging, thus providing a foundation for future modifications.

Cytolytic peptides are an emerging class of promising cancer therapeutics shown to overcome drug resistance. They eliminate cancer cells via disruption of the phospholipid bilayer of cell membranes, a mechanism that differentiates it from traditional treatments. However, applications of lytic peptides via systematic administration are hampered by nonspecific toxicity. Here, we describe activatable, masked lytic peptides that are conjugated with anionic peptides via a cleavable linker sensitive to matrix metalloproteinases (Ac-w-βA-e8-XPLG*LAG-klUklUkklUklUk-NH2; lower case letters in the sequences represent D-amino-acids, U=Aib, α-aminoisobutyric acid, *cleavage site). The peptides were activated upon being introduced into the triple negative breast cancer cell line MDA-MB-231, which overexpresses secreted matrix metalloproteinases, to selectively cleave the peptide linker. Our results indicate that the activatable design could be applied to improve the targeting ability of lytic peptides.

An easily accessible fluorescent dye, FEB, which has a high fluorescence quantum yield and is suitable for in vivo tumour imaging is reported.

In some cases, helical peptides stabilized by an i, i + 7 tether exhibit better target binding and cellular functions compared to their i, i + 4 analogues. Herein, we carried out a systematic study of the effects of an in-tether chiral center on the i, i + 7 system. We screened the optimal cross linking mode, tether length, in-tether chiral center positions, and absolute configurations. From these studies, we determined that a chiral center of R absolute configuration at the γ-position to the C-terminal of a 10-membered tether could function to efficiently induce helicity of the backbone peptides. This is an important addition to the current i, i + 4 in-tether chiral center induced helicity strategy (CIH strategy), and could have broad biological applications.

We report a beta-hairpin dual stabilizing strategy: a D-proline-lproline (D-Pro-L-Pro) dipeptide as the nucleating turn, and a thioether tether as a side-chain linkage at a precisely designed position to stabilize the beta-hairpin. This method was used to modify the C-terminal beta-hairpin moiety of the plant defensin, pv-defensin, in order to obtain a stabilized peptide with enhanced anti-Candida albicans activity (MIC 84-3.0 mm), high serum stability (50% remaining after 48 h) and low hemolysis (< 10% at 152 mm). This modified peptide penetrated the C. albicans cell membrane within 5 min and showed high activity against clinically isolated antibiotic-resistant C. albicans and Candida glabrata strains.

Defensins are small cationic cysteine rich peptides, which usually contain 18-45 amino acids and possess amphiphilic properties. The term "defensin" was coined as the sequences of rabbit and human leukin/phagocytin molecules were first reported in 1985. Since then, various defensins were isolated and characterized from insects, plants and vertebrates. Using vertebrate defensins as examples, defensins are categorized into three sub-families based on their different patterns of intramolecular disulfide linkages: alpha defensins, beta defensins, and theta defensins. During the past decades, continuous attentions were casted on various defensins for their broad activity against bacteria, fungi and viruses. In this review, we focus on the effect of characteristic intramolecular disulfide bonds on the antimicrobial activity of defensins. The disulfide bonds are important for holding the defensins in their three dimensional structures, while also contribute to their antimicrobial activity and chemotactic activity. This review summarizes the effects of disulfide bonds, their synthetic formation pathways and potential pharmaceutical applications.