Helical cyclic peptide

mRNA display is a powerful, high-throughput technology for discovering novel, peptide ligands for protein targets. A number of methods have been used to expand the chemical diversity of mRNA display libraries beyond the 20 canonical amino acids, including genetic code reprogramming and biorthogonal chemistries. To date, however, there have been few reports using enzymes as biocompatible reagents for diversifying mRNA display libraries. Here, we report the evaluation and implementation of the common industrial enzyme, microbial transglutaminase (mTG), as a versatile biocatalyst for cyclization of mRNA display peptide libraries via lysine-to-glutamine isopeptide bonds...

C5a anaphylatoxin chemotactic receptor 1 (C5aR1) is an important target in anti-inflammatory therapeutics. The cyclic peptide antagonist PMX53 binds to the orthosteric site located in the extracellular vestibule of C5aR1, and the non-peptide antagonist NDT9513727 binds to the allosteric site formed by the middle region of TM3 (trans-membrane helix), TM4, and TM5. We catch a sight of the variational binding mode of PMX53 during the Gaussian accelerated molecular dynamic (GaMD) simulations. In the binary complex of C5aR1 and PMX53, the PMX53 takes a dynamic binding mechanism during the simulation...

OBJECTIVE: To investigate the occurrence and frequency of anti-citrullinated protein antibodies (ACPA) to cyclic citrullinated type II collagen (COL2) epitope with a capacity to bind joint cartilage. METHODS: Luminex immunoassay was used to analyze serum antibody reactivity to 10 COL2-citrullinated peptides (ACC10) and corresponding arginine peptide controls in rheumatoid arthritis (RA), osteoarthritis (OA), and healthy individuals' cohorts. Top ten "promiscuous" sera (cross-reactive with all ACC10) and top ten "private" sera (restrictedly reactive with one ACC10 peptide) from RA and OA cohorts were selected...

An alpha helical turn can be reproduced in a cyclic pentapeptide if the first and fifth amino acid sidechains are correctly joined. Here structural studies (CD, NMR, in silico ) reveal why N -methylation at positions not involved in hydrogen bonds disrupts helicity whereas ester bonds can maintain helicity and promote greater cell uptake.

Aggregation of β-amyloid (Aβ) peptide is one of the hallmarks of Alzheimer's disease (AD) which results in chronic and progressive neurodegeneration of the brain. A recent study by our group have shown the ability of cyclic disulfide-rich peptides ("cyclotides") isolated from a medicinal plant, Clitoria ternatea , to inhibit the aggregation of Aβ peptides and reduce oxidative stress caused by reactive oxygen species using in vivo models of transgenic Caenorhabditis elegans . In the present study, through extensive computational docking and multi-ns molecular dynamics (MD) simulation, we evaluated if cyclotides can stably bind to Aβ molecules and/or destabilize the Aβ fibril by preventing conformational changes from α-helical to β-sheet rich structures...

Medium-sized peptides are expected as a next-generation drug discovery modality because they combine the properties of conventional small-molecule drugs and biopharmaceuticals. Nonetheless, peptides are easily degraded by digestive enzymes such as protease in the body, which could be problematic for the development of peptide-based drugs. To overcome such a problem, peptide-based foldamers containing non-proteinogenic amino acids or cyclized peptides have been reported. In addition, peptides must form stable secondary structures and their side chains should be correctly positioned to exert their bioactivity...

Lanthipeptides are a class of cyclic peptides characterized by the presence of one or more lanthionine (Lan) or methyllanthionine (MeLan) thioether rings. These cross-links are produced by α,β-unsaturation of Ser or Thr residues in peptide substrates by dehydration, followed by a Michael-type conjugate addition of Cys residues onto the dehydroamino acids. Lanthipeptides may be broadly classified into at least five different classes, and the biosynthesis of classes I-IV lanthipeptides requires catalysis by LanC cyclases that control both the site-specificity and the stereochemistry of the conjugate addition...

Tailored transmembrane alpha-helical pores with desired structural and functional versatility have promising applications in nanobiotechnology. Herein, we present a transmembrane pore DpPorA, based on the natural pore PorACj, built from D-amino acid α-helical peptides. Using single-channel current recordings, we show that DpPorA peptides self-assemble into uniform cation-selective pores in lipid membranes and exhibit properties distinct from their L-amino acid counterparts. DpPorA shows resistance to protease and acts as a functional nanopore sensor to detect cyclic sugars, polypeptides, and polymers...

Cyclic peptides that modulate protein-protein interactions can be valuable therapeutic candidates if they can be delivered intact to their target proteins in cells. Here we systematically compare the effects of different helix-inducing cyclization constraints on the capacity of a macrocyclic peptide component to confer α-helicity, protein-binding affinity, resistance to degradative proteases and cell uptake to a 12-residue peptide fragment of tumor suppressor protein p53. We varied the helix-inducing constraint (hydrocarbon, lactam, aliphatic or aromatic thioether, etc...

The main challenge in inhibiting protein-protein interactions (PPI) for therapeutic purposes is designing molecules that bind specifically to the interaction hotspots. Adding to the complexity, such hotspots can be within both structured and disordered interaction interfaces. To address this, we present a strategy for inhibiting the structured and disordered hotspots of interactions using chimeric peptides that contain both structured and disordered parts. The chimeric peptides we developed are comprised of a cyclic structured part and a disordered part, which target both disordered and structured hotspots...

Based on the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, we have generated and characterized truncated peptide variants of LCB1, which present only two of the three LCB1 helices, and which fully retained the virus neutralizing potency against different SARS-CoV-2 variants of concern (VOC). This antiviral activity was even 10-fold stronger for a cyclic variant of the two-helix peptides, as compared to the full-length peptide...

Inhibition of amyloid-β peptide (Aβ) aggregation is a promising therapeutic strategy for Alzheimer's disease (AD), as Aβ aggregation is generally believed to trigger AD pathology. Pre-fibril Aβ-oligomers induce membrane disruption and are crucial to neurotoxicity. We have previously designed a short peptide called cyclic helical amyloid surface inhibitor (cHASI) that can selectively bind to the Aβ fibril surface. Here, we use cHASI to efficiently inhibit the surface-catalysed secondary nucleation process of Aβ in a lipid membrane environment...

Amphipathic α-helical peptides have been reported to form discoidal particles or nanodiscs with phospholipids, in which a lipid bilayer patch is encircled by peptides. Peptide-based nanodiscs have broad applicability because of their ease of preparation, size flexibility, and structural plasticity. We previously revealed that the nanodiscs formed by apolipoprotein-A-I-derived peptide 18A showed temperature-dependent structural destabilization above the gel-to-liquid-crystalline phase transition temperature of the lipid bilayer...

<p class="Abstract" style="margin: 0in 0in 0.25in; text-align: justify; line-height: 11.25pt; font-size: 8pt; font-family: Arial, sans-serif; color: rgb(0, 0, 0);">Aromatic groups are key mediators of protein-membrane association at cell surfaces, contributing to hydrophobic effects and pi-membrane interactions. Here we show electrostatic and hydrophobic influences of aromatic ring substituents on membrane affinity and cell uptake of helical, cyclic and cell penetrating peptides. Hydrophobicity is important, but subtle changes in electrostatic surface potential, dipoles and polarizability also enhance association with phospholipid membranes and cell uptake...

SOCS3 (suppressor of cytokine signaling 3) protein suppresses cytokine-induced inflammation and its deletion in neurons or immune cells increases the pathological growth of blood vessels. Recently, we designed several SOCS3 peptidomimetics by assuming as template structures the interfacing regions of the ternary complex constituted by SOCS3, JAK2 (Janus Kinase 2) and gp130 (glycoprotein 130) proteins. A chimeric peptide named KIRCONG chim, including non-contiguous regions demonstrated able to bind to JAK2 and anti-inflammatory and antioxidant properties in VSMCs (vascular smooth muscle cells)...

Peptides and pseudopeptides show distinct self-assembled nanostructures such as fibers, nanotubes, vesicles, micelles, toroids, helices and rods. The formation of such molecular communities through the collective behavior of molecules is not fully understood at a molecular level. All these self-assembled nanostructured materials have a wide range of applications such as drug delivery, gene delivery, biosensing, bioimaging, catalysis, tissue engineering, nano-electronics and sensing. Self-assembly is one of the most efficient and a simple strategy to generate complex functional materials...

Pore-forming alpha-helical proteins are well known for their dynamic assembly mechanism and it has been challenging to delineate the pore-forming structures in membranes. Previously, attempts have been made to elucidate their assembly mechanism and there is a large gap due to complex pathways by which these membrane-active pores impart their effect. Here we demonstrate a multi-step structural assembly pathway of alpha-helical peptide pores formed by a 37 amino acid synthetic peptide, pPorU, based on the natural porin from Corynebacterium urealyticum using single-channel electrical recordings...

Computational design of antimicrobial peptides (AMPs) is a promising area of research for developing novel agents against drug-resistant bacteria. AMPs are present naturally in many organisms, from bacteria to humans, a time-tested mechanism that makes them attractive as effective antibiotics. Depending on the environment, AMPs can exhibit α-helical or β-sheet conformations, a mix of both, or lack secondary structure; they can be linear or cyclic. Prediction of their structures is challenging but critical for rational design...

A model system is introduced as a general tool to elaborate on orthogonal templation of dynamic covalent ring-opening polymerization (ODC-TROP).  The tool consists of 3 10 helical peptides as unprecedented templates and semicarbazones as orthogonal dynamic covalent linkers.  With difficult-to-control 1,2-dithiolanes, ODC-TROP on the level of short model oligomers occurs with high templation efficiency, increasing and diminishing upon helix stabilization and denaturation, respectively.  Further, an anti-templated conjugate with mispositioned monomers gave reduced templation upon helix twisting...

The global burden of the SARS-CoV-2 pandemic is thought to result from a high viral transmission rate. Here, we consider mechanisms that influence host cell-virus binding between the SARS-CoV-2 spike glycoprotein (SPG) and the human angiotensin-converting enzyme 2 (ACE2) with a series of peptides designed to mimic key ACE2 hot spots through adopting a helical conformation analogous to the N-terminal α1 helix of ACE2, the region experimentally shown to bind to the SARS-CoV-2 receptor-binding domain (RBD). The approach examines putative structure/function relations by assessing SPG binding affinity with surface plasmon resonance (SPR)...