Dan Yang

Black phosphorus quantum dot based novel siRNA delivery systems in human pluripotent teratoma PA-1 cells

As a novel semiconducting material, the inherent, direct, and appreciable band gap endows BP with preferable optical and electronic properties other than graphene and transition metal dichalcogenides. In addition, bio-related applications with equal importance also attract great attention thanks to several inherited advantages of BP including large drug loading capacity, high PDT efficiency, high biocompatibility and degradability. However, to date there is limited research about the biomedical applications of BP. In this study, we reported the engineering of polyelectrolyte polymers coated BP quantum dots (BP-QDs)-based nanocarriers to deliver small interfering RNA (siRNA) into human ovarian teratocarcinoma PA-1 cells. Compared to the commercial delivery reagents, superior transfection efficiency of BP-QD was detected. The expression of the LSD1 (lysine-specific demethylase 1) mRNA in PA-1 cells was significantly suppressed by BP-QDs-LSD1 siRNA complex. Notably, BP-QDs possess excellent biocompatibility and low cytotoxicity even at concentrations as high as 5 mg mL-1. The combination treatment of BP nanodots-LSD1 siRNA complex with NIR light could inhibit the cell growth rate by more than 80%. In conclusion, this is the first application of BP-QDs as gene delivery systems, which shows promising potential for siRNA delivery and photothermal effects in cancer therapy.

Disulfide Bridges in Defensins

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: α defensins, β defensins, and θ 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.

A Thioether‐Stabilized d‐Proline–l‐Proline‐Induced β‐Hairpin Peptide of Defensin Segment Increases Its Anti‐Candida albicans Ability

We report a β‐hairpin dual stabilizing strategy: a d‐proline‐l‐proline (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 β‐hairpin. This method was used to modify the C‐terminal β‐hairpin moiety of the plant defensin, pv‐defensin, in order to obtain a stabilized peptide with enhanced anti‐Candida albicans activity (MIC 84–3.0u2005μm), high serum stability (50u2009% remaining after 48u2005h) and low hemolysis (<10u2009% at 152u2005μm). This modified peptide penetrated the C.u2005albicans cell membrane within 5u2005min and showed high activity against clinically isolated antibiotic‐resistant C.u2005albicans and Candida glabrata strains.

Thioether-derived Macrocycle for Peptide Secondary Structure Fixation

Recently, we developed methods to stabilize peptides into various secondary structures, including α-helix, type III turn and β-hairpin via proper thioether based macrocyclization. These conformationally constrained peptidomimetics confer enhanced biophysical properties and provide a valuable avenue towards clinically-relevant therapeutic molecules. In this personal account, thioether-derived macrocyclization methods developed by our group for stabilization of α-helix, type-III β turn and β-hairpin conformations are discussed.

The development of activatable lytic peptides for targeting triple negative breast cancer

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.

Stabilized β-Hairpin Peptide Inhibits Insulin Degrading Enzyme

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.