Peptide-Drug Conjugate with Statistically Designed Transcellular Peptide for Psoriasis-Like Inflammation.

Peptide-drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, physicochemical criteria based on cell-penetrating peptides are employed to design transcellular peptides derived from an antimicrobial peptides library. Among the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, it is found that 6-Paradol (PAR) exhibits inhibitory activity against phosphodiesterase 4, which can be utilized for an anti-inflammatory PDC. The transcellular PDC (SDT7-conjugated with PAR, named TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular PDCs (TDCs) as a promising approach for the treatment of inflammatory skin disorders.

Effect of Secondary Structures on the Adsorption of Peptides onto Hydrophobic Solid Surfaces Revealed by SALDI-TOF and MD Simulations.

The adsorption of peptides and proteins on hydrophobic solid surfaces has received considerable research attention owing to their wide applications to biocompatible nanomaterials and nanodevices, such as biosensors and cell adhesion materials with reduced nanomaterial toxicity. However, fundamental understandings about physicochemical hydrophobic interactions between peptides and hydrophobic solid surfaces are still unknown. In this study, we investigate the effect of secondary structures on adsorption energies between peptides and hydrophobic solid surfaces via experimental and theoretical analyses using surface-assisted laser desorption/ionization-time-of-flight (SALDI-TOF) and molecular dynamics (MD) simulations. The hydrophobic interactions between peptides and hydrophobic solid surfaces measured via SALDI-TOF and MD simulations indicate that the hydrophobic interaction of peptides with random coil structures increased more than that of peptides with an α-helix structure when polar amino acids are replaced with hydrophobic amino acids. Additionally, our study sheds new light on the fundamental understanding of the hydrophobic interaction between hydrophobic solid surfaces and peptides that have diverse secondary structures.

Nature-Inspired Construction of Two-Dimensionally Self-Assembled Peptide on Pristine Graphene.

Peptide assemblies have received significant attention because of their important role in biology and applications in bionanotechnology. Despite recent efforts to elucidate the principles of peptide self-assembly for developing novel functional devices, peptide self-assembly on two-dimensional nanomaterials has remained challenging. Here, we report nature-inspired two-dimensional peptide self-assembly on pristine graphene via optimization of peptide-peptide and peptide-graphene interactions. Two-dimensional peptide self-assembly was designed based on statistical analyses of >104 protein structures existing in nature and atomistic simulation-based structure predictions. We characterized the structures and surface properties of the self-assembled peptide formed on pristine graphene. Our study provides insights into the formation of peptide assemblies coupled with two-dimensional nanomaterials for further development of nanobiocomposite devices.

The Orientations of Large Aspect-Ratio Coiled-Coil Proteins Attached to Gold Nanostructures.

Methods for patterning biomolecules on a substrate at the single molecule level have been studied as a route to sensors with single-molecular sensitivity or as a way to probe biological phenomena at the single-molecule level. However, the arrangement and orientation of single biomolecules on substrates has been less investigated. Here, the arrangement and orientation of two rod-like coiled-coil proteins, cortexillin and tropomyosin, around patterned gold nanostructures is examined. The high aspect ratio of the coiled coils makes it possible to study their orientations and to pursue a strategy of protein orientation via two-point attachment. The proteins are anchored to the surfaces using thiol groups, and the number of cysteine residues in tropomyosin is varied to test how this variation affects the structure and arrangement of the surface-attached proteins. Molecular dynamics studies are used to interpret the observed positional distributions. Based on initial studies of protein attachment to gold post structures, two 31-nm-long tropomyosin molecules are aligned between the two sidewalls of a trench with a width of 68 nm. Because the approach presented in this study uses one of twenty natural amino acids, this method provides a convenient way to pattern biomolecules on substrates using standard chemistry.