A Photoresponsive Hybrid of Viruses and Supramolecular Peptide Fibers for Multidimensional Control of Patterning and Infection.

Viruses are versatile colloidal materials in their biofunctions, monodispersed and periodic structures, and high surface designability. For expanding the applicability of virus-based materials, spatiotemporally controlled immobilization and dispersion of viruses with retained activity should be useful, though control of the dynamic nature of viruses hybridized with commonly used polymers has been difficult due to their strong interactions. Here, we report a self-assembling peptide (A2Az) enabling photo control of adhesion and dispersion of M13 bacteriophage virus (M13 phage) and successfully demonstrate patterning of localization and infection of the virus.

Metal-Responsive Up-Regulation of Bifunctional Disulfides for Suppressing Protein Misfolding and Promoting Oxidative Folding.

The stress-responsive up-regulation process is a sophisticated biological response to maintain cellular homeostasis. In intracellular anti-oxidant systems, the expression level of oxidoreductases is up-regulated under oxidative stress, mitigating oxidative damage on biomolecules and enhancing protein folding capacity. Herein, inspired by the biological system, we developed a synthetic folding promotor whose reactivity is up-regulated under stress conditions.

Ca-triggered allosteric catalysts crosstalk with cellular redox systems through their foldase- and reductase-like activities.

Effective chemical catalysts can artificially control intracellular metabolism. However, in conventional catalytic chemistry, activity and cytotoxicity have a trade-off relationship; thus, driving catalysts in living cells remains challenging. To overcome this critical issue at the interface between catalytic chemistry and biology, we developed cell-driven allosteric catalysts that exert catalytic activity at specific times.

Ligand Design with Accelerated Disulfide Formation with Serum Albumin to Extend Blood Retention.

We proposed a novel ligand for the interaction with human serum albumin (HSA) to extend the blood half-life of small molecular weight therapeutics. The ligand features an alkyl chain and an activated disulfide to allow binding to the hydrophobic pockets of HSA and the formation of disulfide to Cys34 of HSA, thereby minimizing the initial renal clearance. The dual nature of the ligand-HSA bonding was expected to give the ligand long blood retention.

Redox-active chemical chaperones exhibiting promiscuous binding promote oxidative protein folding under condensed sub-millimolar conditions.

Proteins form native structures through folding processes, many of which proceed through intramolecular hydrophobic effect, hydrogen bond and disulfide-bond formation. , protein aggregation is prevented even in the highly condensed milieu of a cell through folding mediated by molecular chaperones and oxidative enzymes. Chemical approaches to date have not replicated such exquisite mediation.

Boosting the enzymatic activity of CxxC motif-containing PDI family members.

Compounds harboring high acidity and oxidizability of thiol groups permit tuning the redox equilibrium constants of CxxC sites of members of the protein disulphide isomerase (PDI) family and thus can be used to accelerate folding processes and increase the production of native proteins by minimal loading in comparison to glutathione.

ROS-Responsive Methionine-Containing Amphiphilic Peptides Impart Enzyme-Triggered Phase Transition and Antioxidant Cell Protection.

Reactive oxygen species (ROS) are produced by cellular activities, such as metabolism and immune response, and play important roles in cell signaling and homeostasis. However, overproduced ROS causes irreversible damage to nucleic acids and membrane lipids, supporting genetic mutations and enhancing the effects of aging. Cells defend themselves against ROS using antioxidant systems based on redox-active sulfur and transition metals.

Activator of KAT3 histone acetyltransferase family ameliorates a neurodevelopmental disorder phenotype in the syntaxin 1A ablated mouse model.

Syntaxin-1A (stx1a) repression causes a neurodevelopmental disorder phenotype, low latent inhibition (LI) behavior, by disrupting 5-hydroxytryptaminergic (5-HTergic) systems. Herein, we discovered that lysine acetyltransferase (KAT) 3B increases stx1a neuronal transcription and TTK21, a KAT3 activator, induces stx1a transcription and 5-HT release in vitro. Furthermore, glucose-derived CSP-TTK21 could restore decreased stx1a expression, 5-HTergic systems in the brain, and low LI in stx1a (+/-) mice by crossing the blood-brain barrier, whereas the KAT3 inhibitor suppresses stx1a expression, 5-HTergic systems, and LI behaviors in wild-type mice.

Enzymatic and synthetic regulation of polypeptide folding.

Proper folding is essential for the biological functions of all proteins. The folding process is intrinsically error-prone, and the misfolding of a polypeptide chain can cause the formation of toxic aggregates related to pathological outcomes such as neurodegenerative disease and diabetes. Chaperones and some enzymes are involved in the cellular proteostasis systems that assist polypeptide folding to diminish the risk of aggregation.

Rapid Synthesis of Chiral Figure-Eight Macrocycles Using a Preorganized Natural Product-Based Scaffold.

Chiral D -symmetric figure-eight shaped macrocycles are promising scaffolds for amplifying the chiroptical properties of π-conjugated systems. By harnessing the inherent and adaptable conformational dynamics of a chiral C -symmetric bispyrrolidinoindoline (BPI) manifold, we developed an enantio-divergent modular synthetic platform to rapidly generate a diverse range of chiral macrocycles, spanning from 14- to 66-membered rings, eliminating the need for optical resolution. Notably, a 32-membered figure-eight macrocycle showed excellent circularly polarized luminescence (CPL: |g |=1.

Semi-enzymatic acceleration of oxidative protein folding by -methylated heteroaromatic thiols.

We report the first example of a synthetic thiol-based compound that promotes oxidative protein folding upon 1-equivalent loading to the disulfide bonds in the client protein to afford the native form in over 70% yield. -Methylation is a central post-translational processing of proteins for regulating functions including chaperone activities. Despite the universally observed biochemical reactions in nature, -methylation has hardly been utilized in the design, functionalization, and switching of synthetic bioregulatory agents, particularly folding promotors.

Self-assembling materials functionalizing bio-interfaces of phospholipid membranes and extracellular matrices.

This Feature Article focuses on recent studies on the development of self-assembling materials that mimic and control dynamic bio-interfaces. Extracellular matrix (ECM) is a fundamental tissue at the cellular interface constructed by networks of fibrous proteins, which regulates a variety of cellular activities. Reconstruction of ECM has been demonstrated by self-assembling peptides.

Endocytosis-Like Vesicle Fission Mediated by a Membrane-Expanding Molecular Machine Enables Virus Encapsulation for In Vivo Delivery.

Biological membranes are functionalized by membrane-associated protein machinery. Membrane-associated transport processes, such as endocytosis, represent a fundamental and universal function mediated by membrane-deforming protein machines, by which small biomolecules and even micrometer-size substances can be transported via encapsulation into membrane vesicles. Although synthetic molecules that induce dynamic membrane deformation have been reported, a molecular approach enabling membrane transport in which membrane deformation is coupled with substance binding and transport remains critically lacking.

ROS-Triggered Gel-Sol Transition and Kinetics-Controlled Cargo Release by Methionine-Containing Peptides.

The gel-sol transition of self-assembling peptides is a useful switch for environment-dependent drug release. For their applications, kinetics control of the responses is important for matching the velocity of release to the target biological events. Here we demonstrate the chemical control of redox-triggered gel-sol transition kinetics of self-assembling peptides by altering the amino acid sequence.

Cell-Penetrating Peptide-Peptide Nucleic Acid Conjugates as a Tool for Protein Functional Elucidation in the Native Bacterium.

Approximately 30% or more of the total proteins annotated from sequenced bacteria genomes are annotated as hypothetical or uncharacterized proteins. However, elucidation on the function of these proteins is hindered by the lack of simple and rapid screening methods, particularly with novel or hard-to-transform bacteria. In this report, we employed cell-penetrating peptide (CPP) -peptide nucleotide acid (PNA) conjugates to elucidate the function of such uncharacterized proteins in vivo within the native bacterium.

Cysteine-based protein folding modulators for trapping intermediates and misfolded forms.

Folding is a key process to form functional conformations of proteins. Folding on-pathway intermediates leads to the formation of native structures, while folding through off-pathways affords non-native and disease-causing forms. Trapping folding intermediates and misfolded forms is important for investigating folding mechanisms and disease-related biological properties of the misfolded proteins.

Self-assembling Molecular Medicine for the Subacute Phase of Ischemic Stroke.

Ischemic stroke leads to acute neuron death and forms an injured core, triggering delayed cell death at the penumbra. The impaired brain functions after ischemic stroke are hardly recovered because of the limited regenerative properties. However, recent rodent intervention studies manipulating the extracellular environments at the subacute phase shed new light on the regenerative potency of the injured brain.

Stabilization of bicelles using metal-binding peptide for extended blood circulation.

A metal-binding peptide appending cholic acid, Chol-MBP, formed bicelles by mixing with 1,2-dipalmitoyl--3-phosphorylcholine (DPPC). Coordination of Chol-MBP with Cu stabilized DPPC bicelles against dilution and contamination of serum proteins, enabling extended blood circulation. This study demonstrates an effective supramolecular design of phospholipid bicelles with enhanced stability useful for membrane-based biomaterials.

Critical Side Chain Effects of Cell-Penetrating Peptides for Transporting Oligo Peptide Nucleic Acids in Bacteria.

Of various methods for delivering functional molecules into cells, a chemical approach using cell-penetrating peptides (CPPs) is facile and highly efficient. Currently, however, there are few examples of CPPs highly efficient with bacteria in contrast to CPPs targeting animal cells, and thus our understanding of the structural effects of these bacteria-efficient CPPs, termed as BCPPs, on permeation efficiency is limited. Herein, we report a comprehensive investigation on the permeation efficiencies of cationic short peptides through bacterial cell membranes.

Efficient protein incorporation and release by a jigsaw-shaped self-assembling peptide hydrogel for injured brain regeneration.

During injured tissue regeneration, the extracellular matrix plays a key role in controlling and coordinating various cellular events by binding and releasing secreted proteins in addition to promoting cell adhesion. Herein, we develop a cell-adhesive fiber-forming peptide that mimics the jigsaw-shaped hydrophobic surface in the dovetail-packing motif of glycophorin A as an artificial extracellular matrix for regenerative therapy. We show that the jigsaw-shaped self-assembling peptide forms several-micrometer-long supramolecular nanofibers through a helix-to-strand transition to afford a hydrogel under physiological conditions and disperses homogeneously in the hydrogel.

Supramolecular Transmembrane Ion Channels Formed by Multiblock Amphiphiles.

Transmembrane proteins located within biological membranes play a crucial role in a variety of important cellular processes, such as energy conversion and signal transduction. Among them, ion channel proteins that can transport specific ions across the biological membranes are particularly important for achieving precise control over those processes. Strikingly, approximately 20% of currently approved drugs are targeted to ion channel proteins within membranes.

Hydrogel-Stiffening and Non-Cell Adhesive Properties of Amphiphilic Peptides with Central Alkylene Chains.

Invited for the cover of this issue is the group of Takahiro Muraoka at Tokyo University of Agriculture and Technology and collaborators. The image depicts nanofiber formation of an amphiphilic peptide with a central alkylene chain that shows non-cell adhesive properties. Read the full text of the article at 10.

Hydrogel-Stiffening and Non-Cell Adhesive Properties of Amphiphilic Peptides with Central Alkylene Chains.

Amphiphilic peptides bearing terminal alkyl tails form supramolecular nanofibers that are increasingly used as biomaterials with multiple functionalities. Insertion of alkylene chains in peptides can be designed as another type of amphiphilic peptide, yet the influence of the internal alkylene chains on self-assembly and biological properties remains poorly defined. Unlike the terminal alkyl tails, the internal alkylene chains can affect not only the hydrophobicity but also the flexibility and packing of the peptides.