Structure Of Peptide Research Articles

Strategy for improving circular dichroism spectra deconvolution accuracy for macrocyclic peptides in drug discovery

Peptide therapeutics have emerged as an appealing modality in the pharmaceutical industry. Understanding peptide conformation in solution remains one of the most critical areas for peptide drug development. Circular dichroism (CD) spectroscopy is a useful technique to study the secondary structure of proteins and peptides, but the current approaches are limited to protein-focused models to predict high-order structures of peptides, and the models were built based on X-ray crystallography instead of solution-based technique, as a result, such models may have poor predictions for peptides. In this study, we present a novel CD deconvolution model to determine peptide conformation in solution. To quantitatively obtain secondary structure information using CD, a calibration model is needed beforehand to establish the relationship between each secondary structure feature and the corresponding CD response. A reference set containing the majority of cyclic peptides with known structures from solution-state NMR spectroscopy was used to build the calibration model for CD deconvolution. Improved prediction accuracy on the secondary structure determination for cyclic peptides was achieved by this model compared to the commercial standard model using commercially available platforms. This new CD deconvolution method is crucial for peptide conformational analysis in solution, and has the potential to greatly accelerate peptide drug candidate optimization in the pharmaceutical drug discovery field.

Target-Specific De Novo Peptide Binder Design with DiffPepBuilder.

Despite the exciting progress in target-specific de novo protein binder design, peptide binder design remains challenging due to the flexibility of peptide structures and the scarcity of protein-peptide complex structure data. In this study, we curated a large synthetic data set, referred to as PepPC-F, from the abundant protein-protein interface data and developed DiffPepBuilder, a de novo target-specific peptide binder generation method that utilizes an SE(3)-equivariant diffusion model trained on PepPC-F to codesign peptide sequences and structures. DiffPepBuilder also introduces disulfide bonds to stabilize the generated peptide structures. We tested DiffPepBuilder on 30 experimentally verified strong peptide binders with available protein-peptide complex structures. DiffPepBuilder was able to effectively recall the native structures and sequences of the peptide ligands and to generate novel peptide binders with improved binding free energy. We subsequently conducted de novo generation case studies on three targets. In both the regeneration test and case studies, DiffPepBuilder outperformed AfDesign and RFdiffusion coupled with ProteinMPNN, in terms of sequence and structure recall, interface quality, and structural diversity. Molecular dynamics simulations confirmed that the introduction of disulfide bonds enhanced the structural rigidity and binding performance of the generated peptides. As a general peptide binder de novo design tool, DiffPepBuilder can be used to design peptide binders for given protein targets with three-dimensional and binding site information.

When can we trust structural models derived from pair distribution function measurements?

The pair distribution function (PDF) is an important metric for characterising structure in complex materials, but it is well known that meaningfully different structural models can sometimes give rise to equivalent PDFs. In this paper, we discuss the use of model likelihoods as a general approach for discriminating between such homometric structure solutions. Drawing on two main case studies-one concerning the structure of a small peptide and the other amorphous calcium carbonate-we show how consideration of model likelihood can help drive robust structure solution, even in cases where the PDF is particularly information-poor. The obvious thread of these individual case studies is the potential role for machine-learning approaches to help guide structure determination from the PDF, and our paper finishes with some forward-looking discussion along these lines.

Discovery of Novel Nonpeptidic Proteasome Inhibitors Using Covalent Virtual Screening and Biological Evaluation.

Many reported proteasome inhibitors, including the three clinically approved inhibitors, bortezomib, carfilzomib, and ixazomib, have peptidic structures. In this study, using a hybrid and versatile strategy for covalent virtual screening by combining warhead screening and preprocessing with GOLD and CovDock software that were applied to the ZINC virtual library, we identified multiple proteasome inhibitors with new nonpeptidic structural scaffolds. Proteasome inhibition assays confirmed the inhibitory activities of these new compounds. These results demonstrate the effectiveness of our computational strategy for large-scale covalent virtual screening. Furthermore, these identified proteasome inhibitors may serve as starting points for the development of a new class of nonpeptidic therapeutic agents.

Characterization of cyclotides Mra30 and cycloviolacin O17 derived from Viola dalatensis Gadnep.

Bacteria threaten human and animal health, and standard antibiotics no longer effective. Antibiotic-resistant microorganisms can make infection treatment challenging and perhaps fail. Investigating the attributes of cyclotide, a peptide with promising antibacterial properties that holds great potential in the field of antibiotic research. The structure of these cyclic peptides involves six conserved cysteine residues that form three disulfide bonds, resulting in a cyclic cystine knot (CCK). This feature guarantees their durability when exposed to changes in temperature, chemicals, and enzymatic degradation. The two cyclotides, cycloviolacin O17 and mra30, were obtained from Viola dalatensis Gadnep through a series of techniques including the use of a 50% acetonitrile/49% miliQ water/1% formic acid solution for extraction, ammonium salt precipitation, RP-HPLC purification and sequence identification by LC-MS/MS. These cyclotides exhibit antibacterial effects on specific strains of bacteria like Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa at a concentration of 0.2mg/mL, leading to inhibition zones ranging from 10 to 14mm. In addition, the disulfide bonds play a crucial role in the antibacterial function of cyclotides. Disrupting the disulfide bonds through ankylation reaction results in the loss of antibacterial properties in the cyclotides (cyO17 and mra30). The minimum inhibitory concentration (MIC) values of mra30 and cyO17 are significantly low, ranging from 0.1 to 0.6 µM. These values are approximately three times lower than the MIC values observed in salt precipitation samples.

Effects of papain hydrolysate of Pseudosciaena crocea roe on the physical and oxidative stability of water-in-oil emulsions

This study investigates the effects of hydrolysates from Pseudosciaena crocea roe on the physical and oxidative stability of oil-in-water emulsions, emphasizing the structure-activity relationship between peptide structure and emulsifying properties. The results showed that, compared to other proteases, hydrolysates prepared with papain (PCRHs) at moderate degrees of hydrolysis (DH 4.68% and 6.8%) exhibited superior emulsifying activity index (EAI) and emulsifying stability index (ESI). PCRHs with DH of 4.68%, 6.8% formed smaller particle sizes (89.8 ± 3.52 nm, 112 ± 2.65 nm) and more stable emulsions. EAI and ESI of PCRHs were significantly negatively correlated with emulsion particle size and significantly positively correlated with surface hydrophobicity, amino acid composition, relative molecular mass, random coil content and total sulfhydryl groups. Additionally, although PCRHs with DH of 4.68% produced smaller and more stable emulsion particles, PCRHs with DH of 6.8% significantly inhibited primary and secondary lipid oxidation products formation. Correlation analysis revealed that emulsions with smaller particle sizes exhibited poorer oxidative stability, and secondary volatile oxidation products better reflected the oxidative stability of emulsions. Therefore, hydrolysates from Pseudosciaena crocea roe protein with moderate hydrolysis, particularly PCRHs with DH of 6.8%, demonstrate potential as natural emulsifiers to maintain the physical and oxidative stability of oil-in-water emulsions.

Stapled Peptides: An Innovative and Ultimate Future Drug Offering a Highly Powerful and Potent Therapeutic Alternative.

Peptide-based therapeutics have traditionally faced challenges, including instability in the bloodstream and limited cell membrane permeability. However, recent advancements in α-helix stapled peptide modification techniques have rekindled interest in their efficacy. Notably, these developments ensure a highly effective method for improving peptide stability and enhancing cell membrane penetration. Particularly in the realm of antimicrobial peptides (AMPs), the application of stapled peptide techniques has significantly increased peptide stability and has been successfully applied to many peptides. Furthermore, constraining the secondary structure of peptides has also been proven to enhance their biological activity. In this review, the entire process through which hydrocarbon-stapled antimicrobial peptides attain improved drug-like properties is examined. First, the essential secondary structural elements required for their activity as drugs are validated, specific residues are identified using alanine scanning, and stapling techniques are strategically incorporated at precise locations. Additionally, the mechanisms by which these structure-based stapled peptides function as AMPs are explored, providing a comprehensive and engaging discussion.

Polarized benzene rings can promote the interaction between CaM and the CaMBD region of nNOS.

The neuronal nitric oxide synthase (nNOS) subtype of nitric oxide synthase (NOS) is an enzyme required for learning and memory. Overactivation of nNOS can lead to oxidative/nitrite stress, which is complicit in the pathophysiology of various neurological and psychiatric disorders. Previous studies have shown that calmodulin (CaM) forms complexes with Ca2+ and binds to the calmodulin-binding domain (CaMBD) of nNOS, thereby upregulating its catalytic activity in hippocampal neurons. To date, there has been no explanation for the non-covalent interactions in the CaMBD-CaM binding structure model of nNOS. In this study, we aimed to investigate the intrinsic factors involved in the binding of CaM to NOS-CaMBD and designed interfering peptides based on the N0 peptide structure of the original nNOS-CaMBD sequence: N1 (obtained from the L734F mutation), N2 (obtained from the F731Y and F740Y mutations), and N3 (obtained from the F731L, V738L, and F740L mutations). We employed homology modeling to construct six CaM-peptide complex models, aiming to elucidate the roles of key amino acid residues within the N0 peptide in its interaction with CaM by means of molecular dynamics simulations. The effect of the peptides on the activation and release of NO by nNOS in neurons was assessed using murine primary neuronal cells. When measuring neuronal NO content, it was found that adding N2 and N3 to cultivated neurons significantly increased nNOS activity, leading to the increased NO production. We found that interfering peptides could stably bind to CaM. Among them, N2 and CaM exhibited the strongest binding ability, indicating that the polarized benzene ring significantly enhanced the binding between nNOS-CaMBD and CaM. Conversely, the binding ability between N0 and CaM was the weakest, as they exhibited the worst polar contact, weakest hydrogen bonding, and the lowest binding free energy. The simulation results also highlighted several important amino acid residues: The K76 of CaM plays an important role in polar contact and hydrogen bonding formation, the L734 residue suppressed model flexibility to a certain extent and had an adverse effect on the overall binding free energy of the model. These results, compared with the results of cellular NO content, a preliminary verification of the antagonistic competitive mechanism between CaM allosteric activation of nNOS and SUMOylation hyperactivation was performed. In summary, this study explored the ability and mode of action of key residues in nNOS-CaMBD on the binding of interfering peptides to CaM, thereby providing new structural perspectives for the activation of nNOS by CaM and recommendations for drug design targeting the specific inhibition of nNOS.

Non-benzenoid N-aryl oxalamide: synthesis of troponyl-oxalamide peptides by Pd(II)-catalyzed C(sp3)-H functionalization of glycinamides.

Aryl oxalamides are constituents of various promising drug-like molecules. Their aryl groups are derived from the benzenoid aromatic moiety. However, non-benzenoid aromatic molecules, troponoids, are found in various bioactive natural products. It would be thought-provoking to explore non-benzenoid aryl oxalamide derivatives. This report describes the synthesis of N-troponyl-oxalamide peptides by Pd(II)-catalyzed C(sp3)-H functionalization of N-troponyl glycinate peptides. This is the first instance of β-hydride elimination at the palladium complex of N-troponyl glycinates that generates imine in situ, rendering the synthesis of oxalamides. Importantly, the crystal structures of representative oxalamide derivatives form distinctive foldameric structures, such as β-sheet type structures, owing to the presence of additional troponyl carbonyl groups. Hence, these non-benzenoid oxalamides are potential scaffolds for tuning the structure and function of N-troponyl peptides, which could provide innovative avenues of research in the development of emerging structural and functional peptides.

Design, synthesis and biological evaluation of amphiphilic benzopyran derivatives as potent antibacterial agents against multidrug-resistant bacteria

Antimicrobial resistance has emerged as a significant threat to global public health. To develop novel, high efficiency antibacterial alternatives to combat multidrug-resistant bacteria, A total of thirty-two novel amphiphilic benzopyran derivatives by mimicking the structure and function of antimicrobial peptides were designed and synthesized. Among them, the most promising compounds 4h and 17e displayed excellent antibacterial activity against Gram-positive bacteria (MICs = 1–4 μg/mL) with weak hemolytic activity and good membrane selectivity. Additionally, compounds 4h and 17e had rapid bactericidal properties, low resistance frequency, good plasma stability, and strong capabilities of inhibiting and eliminating bacterial biofilms. Mechanistic studies revealed that compounds 4h and 17e could effectively disrupt the integrity of bacterial cell membranes, and accompanied by an increase in intracellular reactive oxygen species and the leakage of proteins and DNA, ultimately leading to bacterial death. Notably, compound 4h exhibited comparable in vivo antibacterial potency in a mouse septicemia model infected by Staphylococcus aureus ATCC43300, as compared to vancomycin. These findings indicated that 4h might be a promising antibacterial candidate to combat antimicrobial resistance.

De Novo Rational Design of Peptide-Based Protein-Protein Inhibitors (Pep-PPIs) Approach by Mapping the Interaction Motifs of the PP Interface and Physicochemical Filtration: A Case on p25-Cdk5-Mediated Neurodegenerative Diseases.

Protein-protein interactions, or PPIs, are a part of every biological activity and have been linked to a number of diseases, including cancer, infectious diseases, and neurological disorders. As such, targeting PPIs is considered a strategic and vital approach in the development of new medications. Nonetheless, the wide and flat contact interface makes it difficult to find small-molecule PP inhibitors. An alternative strategy would be to use the PPI interaction motifs as building blocks for the design of peptide-based inhibitors. Herein, we designed 12-mer peptide inhibitors to target p25-inducing-cyclin-dependent kinase (Cdk5) hyperregulation, a PPI that has been shown to perpetuate neuroinflammation, which is one of the major causal implications of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. We generated a library of 5 062 500 peptide combination sequences (PCS) derived from the interaction motif of Cdk5/p25 PP interface. The 20 amino acids were differentiated into six groups, namely, hydrophobic (aliphatic), aromatic, basic, acidic, unique, and polar uncharged, on the basis of their physiochemical properties. To preserve the interaction motif necessary for ideal binding, de novo modeling of all possible peptide sequence substitutions was considered. A set of filters, backed by the Support Vector Machine (SVM) algorithm, was then used to create a shortlisted custom peptide library that met specific bioavailability, toxicity, and therapeutic relevance, leading to a refined library of 15 PCS. A greedy algorithm and coarse-grained force field were used to predict peptide structure and folding before subsequent modeling studies. Molecular docking was performed to estimate the relative binding affinities, and out of the top hits, Pep15 was subjected to molecular dynamics simulations and binding free-energy calculations in comparison to a known peptide inhibitor with experimental data (template peptide). Interestingly, the identified peptide through our protocol, Pep15, was found to show a significantly higher binding affinity than the reference template peptide (-48.10 ± 0.23 kcal/moland -17.53 ± 0.27 kcal/mol, respectively). In comparison to the template peptide, Pep15 was found to possess a more compact and buried surface area, tighter binding landscape, and reduced conformational variability, leading to enhanced structural and kinetic stability of the Cdk5/p25 complex. Notably, both peptide inhibitors were found to have a minimal impact on the architectural integrity of the Cdk5/p25 secondary structure. Herein, we propose Pep15 as a novel and potentially disruptive peptide drug for Cdk5/p25-mediated neurodegenerative phenotypes that require further clinical investigation. The systematic protocol and findings of this report would serve as a valuable tool in the identification of critical PPI interface reactive residues, designing of analogs, and identification of more potent peptide-based PPI inhibitors.

A Multi-Angle Approach to Predict Peptide-GPCR Complexes: The N/OFQ-NOP System as a Successful AlphaFold Application Case Study.

With nearly 700 structures solved and a growing number of customized structure prediction algorithms being developed at a fast pace, G protein-coupled receptors (GPCRs) are an optimal test case for validating new approaches for the prediction of receptor active state and ligand bioactive conformation complexes. In this study, we leveraged the availability of hundreds of peptide GPCRs in the active state and both classical homology and artificial intelligence (AI) based protein modeling combined with docking and AI-based peptide structure prediction approaches to predict the nociceptin/orphanin FQ-NOP receptor active state complex (N/OFQ-NOPa). The In Silico generated hypotheses were validated via the design, synthesis, and pharmacological characterization of novel linear N/OFQ(1-13)-NH2 analogues, leading to the discovery of a novel antagonist (3B; pKB = 6.63) bearing a single ring-constrained residue in place of the Gly2-Gly3 motif of the N/OFQ message sequence (FGGF). While the experimental validation was ongoing, the availability of the Cryo-EM structure of the predicted complex enabled us to unambiguously validate the generated hypotheses. To the best of our knowledge, this is the first example of a peptide-GPCR complex predicted with atomistic accuracy (full complex Cα RMSD < 1.0 Å) and of the N/OFQ message moiety being successfully modified with a rigid scaffold.

Isolation and characterization of NGFFYamide neuropeptide from Patiria pectinifera pyloric caeca extract

Neuropeptides are small molecules that mediate intercellular signaling and regulate physiological processes. Starfish possess various myoactive neuropeptides, including starfish myorelaxant peptide (SMP) and a calcitonin-type peptide with apical muscle relaxing properties. In this study, we report the purification of a neuropeptide from starfish (Patiria pectinifera) pyloric caeca extract using high-performance liquid chromatography (HPLC) and an in vitro bioassay to screen for fractions and peptides with relaxing effects on P. pectinifera apical muscle preparations. A series of HPLC steps using reversed-phase and cation-exchange columns yielded a purified peptide with muscle-relaxing effects. The purified peptide's structure was determined by LC-MS and Edman degradation, revealing a pentapeptide with an amidated C-terminus (NGFFYamide) and a molecular mass of 646.2930 Da. This is the first report of NGFFYamide purification from P. pectinifera through biochemical methods. The nucleotide sequence encoding the NGFFYamide precursor was determined, showing the presence of a conserved neurophysin domain in the C-terminal region. RT-qPCR results confirmed high expression in radial nerves cord, consistent with previous findings on NG peptides in echinoderms. In vitro pharmacological studies on muscle preparations from P. pectinifera and Asterias amurensis revealed differential relaxing activity of NGFFYamide on apical muscles, while its effects on tube foot preparations were similar in both species. NGFFYamide also induced potent contraction in P. pectinifera cardiac stomach. Comparison of three NG peptides (NGFFYamide, NGFFFamide, and NGIWYamide) on P. pectinifera cardiac stomach revealed varying potency, suggesting class-specific receptor interactions. Tachyphylaxis was observed in P. pectinifera apical muscle but not in A. amurensis, warranting further investigation. Based on these results, it is plausible that NGFFYamide could be involved in regulating locomotion and feeding behavior in P. pectinifera, consistent with findings in Asterias rubens.

Preparation, characterization and microencapsulation of walnut (Juglans regia L.) peptides-zinc chelate.

In this research, a novel kind of walnut (Juglans regia L.) peptides-zinc (Zn-WPs) chelate was obtained using the mass ratio of the walnut peptides (WPs) to ZnSO4.7H2O of 3.5:1 at pH 8.5 and 50°C for 84min, with the chelation rate of 84.5%. In comparison to walnut peptides (WPs), the contents of aspartic acid and glutamic acid in Zn-WPs chelate are approximately 27%, indicating that hydrophilic amino acids predominantly bind with walnut peptides. Following chelation with zinc ions, the ultraviolet-visible (UV) characteristic absorption peak shifted from 213nm to 210nm, while the average particle size of the chelate increased to 8.0±0.14µm, presenting a loose spherical structure under scanning electron microscopy. These findings suggest the formation of new substances. Fourier-transform infrared spectroscopy (FTIR) revealed carboxyl, amino, and peptide bonds as the chelation sites of WPs and zinc. The IC50 of walnut peptides-zinc (Zn-WPs) chelate is 2.91mg/mL, indicative of a favorable DPPH radical scavenging rate. Furthermore, Zn-WPs chelate microcapsules were produced via the spray drying method, achieving an encapsulation rate of 75.67±0.83% under optimal conditions. These microcapsules demonstrate robust stability across diverse environmental conditions. This study underscores the potential of Zn-WPs and its chelate microcapsules to enhance stability and bioactivity under varying circumstances. PRACTICAL APPLICATION: In this study, a new walnut peptide-zinc (Zn-WPs) chelate was prepared. The presence of zinc ions changes the structure and properties of walnut peptides and improves its stability. The production of Zn-WPs chelate microcapsules enables Zn-WPs to have strong in vitro stability under different pH and simulated gastrointestinal digestion conditions. These results provide novel insights for developing the walnut peptides as bioactive ingredients in functional foods.

Genesis and regulation of C-terminal cyclic imides from protein damage.

C-Terminal cyclic imides are post-translational modifications (PTMs) that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail. Here, we characterize the primary and secondary structures of peptides and proteins that promote intrinsic formation of C-terminal cyclic imides in comparison to deamidation, a related form of protein damage. Extrinsic effects from solution properties and stressors on the cellular proteome additionally promote C-terminal cyclic imide formation on proteins like glutathione synthetase (GSS) that are susceptible to aggregation if the protein damage products are not removed by CRBN. This systematic investigation provides insight to the regions of the proteome that are prone to these unexpectedly frequent modifications, the effects of this form of protein damage on protein stability, and the biological role of CRBN.

Ponicidin Promotes Hepatocellular Carcinoma Mitochondrial Apoptosis by Stabilizing Keap1-PGAM5 Complex.

Ponicidin is a diterpenoid with demonstrated antitumor activity in clinical trials. However, the specific function and mechanism of action against hepatocellular carcinoma (HCC) remain unknown. In this study, it is found that ponicidin significantly inhibited the proliferation and migration of HCC cells. It is shown that ponicidin targets Keap1 and promotes the formation of the Keap1-PGAM5 complex, leading to the ubiquitination of PGAM5, using biotin-labeled ponicidin for target fishing and the HuProtTM Human Proteome Microarray V4.0. Ponicidin is found to activate the cysteine-dependent mitochondrial pathway via PGAM5, resulting in mitochondrial damage and ROS production, thereby promoting mitochondrial apoptosis in HepG2 cells. The first in vitro cocrystal structure of the PGAM5 IE 12-mer peptide and the Keap1 Kelch domain is obtained. Using molecular dynamics simulations to confirm the binding of ponicidin to the Keap1-PGAM5 complex. Based on the depth-based dynamic simulation, it is found that ponicidin can induce the tightening of the Keap1-PGAM5 interaction pocket, thereby stabilizing the formation of the protein complex. Finally, it is observed that ponicidin effectively inhibited tumor growth and promoted tumor cell apoptosis in a BALB/c nude mouse xenograft tumor model. The results provide insight into the anti-HCC properties of ponicidin based on a mechanism involving the Keap1-PGAM5 complex.

Development of Xanthoangelol-Derived Compounds with Membrane-Disrupting Effects against Gram-Positive Bacteria.

Infections caused by multidrug-resistant pathogens have emerged as a serious threat to public health. To develop new antibacterial agents to combat such drug-resistant bacteria, a class of novel amphiphilic xanthoangelol-derived compounds were designed and synthesized by mimicking the structure and function of antimicrobial peptides (AMPs). Among them, compound 9h displayed excellent antimicrobial activity against the Gram-positive strains tested (MICs = 0.5-2 μg/mL), comparable to vancomycin, and with low hemolytic toxicity and good membrane selectivity. Additionally, compound 9h demonstrated rapid bactericidal effects, low resistance frequency, low cytotoxicity, and good plasma stability. Mechanistic studies further revealed that compound 9h had good membrane-targeting ability and was able to destroy the integrity of bacterial cell membranes, causing an increase in intracellular ROS and the leakage of DNA and proteins, thus accelerating bacterial death. These results make 9h a promising antimicrobial candidate to combat bacterial infection.

Helical peptide structure improves conductivity and stability of solid electrolytes.

Ion transport is essential to energy storage, cellular signalling and desalination. Polymers have been explored for decades as solid-state electrolytes by either adding salt to polar polymers or tethering ions to the backbone to create less flammable and more robust systems. New design paradigms are needed to advance the performance of solid polymer electrolytes beyond conventional systems. Here the role of a helical secondary structure is shown to greatly enhance the conductivity of solvent-free polymer electrolytes using cationic polypeptides with a mobile anion. Longer helices lead to higher conductivity, and random coil peptides show substantially lower conductivity. The macrodipole of the helix increases with peptide length, leading to larger dielectric constants. The hydrogen bonding of the helix also imparts thermal and electrochemical stability, while allowing for facile dissolution back to monomer in acid. Peptide polymer electrolytes present a promising platform for the design of next-generation ion-transporting materials.

Cyclotides Versus Acyclotides: Discovery, Characterization and Their Potential in Cancer Therapy

AbstractProtein‐ and peptide‐based therapies have emerged as a possible alternative to antibody‐ and small molecule‐ based therapies for treating cancer, aiming to improve drug localization and enhance effectiveness. Peptides such as cyclotides and acyclotides are known for their exceptional stability, which is attributed to the presence of a cystine knot. These peptides exhibit a diverse array of biological activities, making them promising candidates for therapeutic development. Transcriptomics approaches are frequently employed to gain insights into gene organization and identify variations in transcript expression levels. Furthermore, proteomics and NMR spectroscopy techniques are highly regarded as a potent method for analyzing peptide structures. This review offers a thorough examination of the most recent advancements and developments in the methods employed to isolate and characterize the peptides, including purification, proteomics, and transcriptomics. Furthermore, the article thoroughly analyzes the unique structural features of cyclotides and acyclotides, providing valuable insights into their potential groundbreaking applications. The discussion also explores the issuance of numerous patents in the medical and pharmaceutical field, highlighting the growing interest and potential applications of cyclotides in cancer treatment.

Diverse Proteomimetic Frameworks via Rational Design of π-Stacking Peptide Tectons.

Peptide-based frameworks aim to integrate protein architecture into solid-state materials using simpler building blocks. Despite the growing number of peptide frameworks, there are few strategies to rationally engineer essential properties like pore size and shape. Designing peptide assemblies is generally hindered by the difficulty of predicting complex networks of weak intermolecular interactions. Peptides conjugated to polyaromatic groups are a unique case where assembly appears to be strongly driven by π-π interactions, suggesting that rationally adjusting the geometry of the π-stackers could create novel structures. Here, we report peptide elongation as a simple mechanism to predictably tune the angle between the π-stacking groups to produce a remarkable diversity of pore shapes and sizes, including some that are mesoporous. Notably, rapid jumps in pore size and shape can occur with just a single amino acid insertion. The geometry of the π-stacking residues also significantly influences framework structure, representing an additional dimension for tuning. Lastly, sequence identity can also indirectly modulate the π-π interactions. By correlating each of these factors with detailed crystallographic data, we find that, despite the complexity of peptide structure, the shape and polarity of the tectons are straightforward predictors of framework structure. These guidelines are expected to accelerate the development of advanced porous materials with protein-like capabilities.