Membrane-Active All-Hydrocarbon-Stapled α-Helical Amphiphilic Tat Peptides: Broad-Spectrum Antibacterial Activity and Low Incidence of Drug Resistance.

Multidrug resistance against conventional antibiotics has dramatically increased the difficulty of treatment and accelerated the need for novel antibacterial agents. The peptide Tat (47-57) is derived from the transactivating transcriptional activator of human immunodeficiency virus 1, which is well-known as a cell-penetrating peptide in mammalian cells. However, it is also reported that the Tat peptide (47-57) has antifungal activity. In this study, a series of membrane-active hydrocarbon-stapled α-helical amphiphilic peptides were synthesized and evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The impact of hydrocarbon staple, the position of aromatic amino acid residue in the hydrophobic face, the various types of aromatic amino acids, and the hydrophobicity on bioactivity were also investigated and discussed in this study. Among those synthesized peptides, analogues P3 and P10 bearing a l-2-naphthylalanine (Φ) residue at the first position and a Tyr residue at the eighth position demonstrated the highest antimicrobial activity and negligible hemolytic toxicity. Notably, P3 and P10 showed obviously enhanced antimicrobial activity against multidrug-resistant bacteria, low drug resistance, high cell selectivity, extended half-life in plasma, and excellent performance against biofilm. The antibacterial mechanisms of P3 and P10 were also preliminarily investigated in this effort. In conclusion, P3 and P10 are promising antimicrobial alternatives for the treatment of the antimicrobial-resistance crisis.

Development of a Decafluorobiphenyl Cyclized Peptide Targeting the NEMO-IKKα/ß Interaction that Enhances Cell Penetration and Attenuates Lipopolysaccharide-Induced Acute Lung Injury.

Aberrant canonical NF-κB signaling has been implicated in diseases, such as autoimmune disorders and cancer. Direct disruption of the interaction of NEMO and IKKα/ß has been developed as a novel way to inhibit the overactivation of NF-κB. Peptides are a potential solution for disrupting protein-protein interactions (PPIs); however, they typically suffer from poor stability in vivo and limited tissue penetration permeability, hampering their widespread use as new chemical biology tools and potential therapeutics. In this work, decafluorobiphenyl-cysteine SNAr chemistry, molecular modeling, and biological validation allowed the development of peptide PPI inhibitors. The resulting cyclic peptide specifically inhibited canonical NF-κB signaling in vitro and in vivo, and presented positive metabolic stability, anti-inflammatory effects, and low cytotoxicity. Importantly, our results also revealed that cyclic peptides had huge potential in acute lung injury (ALI) treatment, and confirmed the role of the decafluorobiphenyl-based cyclization strategy in enhancing the biological activity of peptide NEMO-IKKα/ß inhibitors. Moreover, it provided a promising method for the development of peptide-PPI inhibitors.

A tunable perfect absorber based on a black phosphorus/bowtie shaped cavity hybrid metasurface.

The practical application of black phosphorus (BP) is limited by its low absorption characteristics. In this work, we propose a perfect absorber based on a BP and bowtie shaped cavity, which has high tunability and excellent optical performance. This absorber effectively increases the light-matter interaction and achieves perfect absorption by using a monolayer BP and a reflector to form a Fabry-Perot cavity. We study the influence of structural parameters on the absorption spectrum and realize the adjustment of frequency and absorption in a certain range. Applying an external electric field on the surface of BP by electrostatic gating, we can change its carrier concentration to control its optical properties. In addition, we can flexibly tune the absorption and Q-factor by varying the polarization direction of incident light. This absorber has promising applications in optical switches, sensing, and slow light, which provides a new perspective for the practical application of BP and a foundation for future research, offering possibilities for more applications.

IPGA: A handy integrated prokaryotes genome and pan-genome analysis web service.

Pan-genomics is one of the most powerful means to study genomic variation and obtain a sketch of genes within a defined clade of species. Though there are a lot of computational tools to achieve this, an integrated framework to evaluate their performance and offer the best choice to users has never been achieved. To ease the process of large-scale prokaryotic genome analysis, we introduce Integrated Prokaryotes Genome and pan-genome Analysis (IPGA), a one-stop web service to analyze, compare, and visualize pan-genome as well as individual genomes, that rids users of installing any specific tools. IPGA features a scoring system that helps users to evaluate the reliability of pan-genome profiles generated by different packages. Thus, IPGA can help users ascertain the profiling method that is most suitable for their data set for the following analysis. In addition, IPGA integrates several downstream comparative analysis and genome analysis modules to make users achieve diverse targets.

Self-assembling modified neuropeptide S enhances nose-to-brain penetration and exerts a prolonged anxiolytic-like effect.

Anxiety disorders are the most common mental diseases and can greatly disrupt everyday life. Although there has been substantial research on anxiety disorders, novel therapeutics are needed. Neuropeptide S (NPS) is a potential therapeutic candidate owing to its strong anxiolytic activity; however, some disadvantages, such as its poor metabolic stability and inability to cross the blood-brain barrier (BBB), limit its use in the clinic. Herein, inspired by nose-to-brain drug delivery strategies, an endogenous 20-amino-acid-long mNPS peptide was modified by incorporating palmitic acid into its functional Lys12 side chain (M-3), which was expected to facilitate nose-to-brain penetration and exert a prolonged anxiolytic-like effect compared to mNPS. We found that M-3 assembled into nanofibers that retained the bioactivity of NPS and exhibited obvious improvements in metabolic stability. Notably, as expected, self-assembled M-3 was able to penetrate into the brain and exert anxiolytic effects. The elevated plus-maze (EPM) results further revealed that M-3 could produce prolonged anxiolytic-like effects in mice. In vivo imaging studies revealed that self-assembled M-3 could be efficiently transported from the nasal cavity to the brain. Furthermore, when intranasally administered, this molecule exhibited a significantly prolonged anxiolytic-like effect, which further illustrated that this molecule has a potent nose-to-brain penetration in vivo. Overall, this self-assembled nanofiber showed potent nose-to-brain penetration ability and prolonged bioactivity.

Hydrocarbon staple constructing highly efficient α-helix cell-penetrating peptides for intracellular cargo delivery.

The effects of all-hydrocarbon cross-linking on the cell-penetrating properties of Tat were systematically investigated. These stapled cell-penetrating peptides were designed to exhibit a cationic secondary amphipathic profile. We found that the hydrophobicity and helical conformation of these hydrocarbon staple peptides correlate well with their cellular uptake efficiency. Our results also revealed that higher affinity to heparan sulfate of the rigid stapled Tat peptides correlated well with the higher cellular uptake compared with non-stapled Tat peptides with flexible charge display. Notably, the stapled Tat peptides showed increased endosomal escape, high proteolytic stability, and low cytotoxicity. Therefore, they present a potent system for the intracellular transport of bioactive cargos.

Dynamically tunable switch and filter in single slot cavity structure.

A single slot cavity coupled with two waveguides has been researched in theory and simulation. The results comparison between theory and simulation shows they agree well. It is found that the lateral displacement S plays an important role in transmission properties. Moreover, increasing the width of the slot cavity results in the emergence of new resonant peaks. At the same time, the shift of the resonant peaks have been explained well. The slot cavity with Kerr nonlinear material can act as a dynamically tunable four channel switch and filter. The single slot cavity has the advantages of simple and compact structure, easy fabrication, and the excellent properties are helpful to control light in photonics circuits.