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Macromolecular Bioscience Dec 2023The unique optical and electronic properties of living systems are impressive. Peptide-based supramolecular self-assembly systems attempt to mimic these properties by... (Review)
Review
The unique optical and electronic properties of living systems are impressive. Peptide-based supramolecular self-assembly systems attempt to mimic these properties by preparation optical/electronic function materials with specific structure through simple building blocks, rational molecular design, and specific kinetic stimulation. From the perspective of building blocks and assembly strategies, the unique optical and electronic properties of peptide-based nanostructures, including peptides self-assembly and peptides regulate the assembly of external function subunits, are systematically reviewed. Additionally, their applications in biomedicine, sensing, and energy storage are also highlighted. This bioinspired peptide-based function material is one of the hot candidates for the new generation of green intellect materials, with many advantages such as biocompatibility, environmental friendliness, and adjustable morphology.
Topics: Nanostructures; Peptides; Kinetics
PubMed: 37466295
DOI: 10.1002/mabi.202300171 -
Molecules (Basel, Switzerland) Oct 2023Peptides are at the cutting edge of contemporary research for new potent, selective, and safe therapeutical agents. Their rise has reshaped the pharmaceutical landscape,... (Review)
Review
Peptides are at the cutting edge of contemporary research for new potent, selective, and safe therapeutical agents. Their rise has reshaped the pharmaceutical landscape, providing solutions to challenges that traditional small molecules often cannot address. A wide variety of natural and modified peptides have been obtained and studied, and many others are advancing in clinical trials, covering multiple therapeutic areas. As the demand for peptide-based therapies grows, so does the need for sustainable and environmentally friendly synthesis methods. Traditional peptide synthesis, while effective, often involves environmentally draining processes, generating significant waste and consuming vast resources. The integration of green chemistry offers sustainable alternatives, prioritizing eco-friendly processes, waste reduction, and energy conservation. This review delves into the transformative potential of applying green chemistry principles to peptide synthesis by discussing relevant examples of the application of such approaches to the production of active pharmaceutical ingredients (APIs) with a peptide structure and how these efforts are critical for an effective green transition era in the pharmaceutical field.
Topics: Peptides; Chemistry Techniques, Synthetic; Pharmaceutical Preparations
PubMed: 37894644
DOI: 10.3390/molecules28207165 -
Pharmacological Research May 2024Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced... (Review)
Review
Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced proteolytic stability, compared to the original peptides, and provides an effective solution to accelerate the rapid development of peptide drugs. Various reviews present peptide stapling chemistries, anchoring residues and one- or two-component cyclization, however, therapeutic stapled peptides have not been systematically summarized, especially focusing on various disease-related targets. This review highlights the latest advances in therapeutic peptide drug development facilitated by the application of stapling technology, including different stapling techniques, synthetic accessibility, applicability to biological targets, potential for solving biological problems, as well as the current status of development. Stapled peptides as therapeutic drug candidates have been classified and analysed mainly by receptor- and ligand-based stapled peptide design against various diseases, including cancer, infectious diseases, inflammation, and diabetes. This review is expected to provide a comprehensive reference for the rational design of stapled peptides for different diseases and targets to facilitate the development of therapeutic peptides with enhanced pharmacokinetic and biological properties.
Topics: Humans; Animals; Peptides; Drug Design
PubMed: 38522761
DOI: 10.1016/j.phrs.2024.107137 -
Soft Matter Nov 2023Modelin-5 (M5-NH) killed with a minimum lethal concentration (MLC) of 5.86 μM and strongly bound its cytoplasmic membrane (CM) with a of 23.5 μM. The peptide adopted...
Modelin-5 (M5-NH) killed with a minimum lethal concentration (MLC) of 5.86 μM and strongly bound its cytoplasmic membrane (CM) with a of 23.5 μM. The peptide adopted high levels of amphiphilic α-helical structure (75.0%) and penetrated the CM hydrophobic core (8.0 mN m). This insertion destabilised CM structure increased lipid packing and decreased fluidity (Δ < 0), which promoted high levels of lysis (84.1%) and cell death. M5-NH showed a very strong affinity ( = 3.5 μM) and very high levels of amphiphilic α-helical structure with cardiolipin membranes (96.0%,) which primarily drove the peptide's membranolytic action against . In contrast, M5-NH killed with an MLC of 147.6 μM and weakly bound its CM with a of 117.6 μM, The peptide adopted low levels of amphiphilic α-helical structure (35.0%) and only penetrated the upper regions of the CM (3.3 mN m). This insertion stabilised CM structure decreased lipid packing and increased fluidity (Δ > 0) and promoted only low levels of lysis (24.3%). The insertion and lysis of the CM by M5-NH showed a strong negative correlation with its lysyl phosphatidylglycerol (Lys-PG) content ( > 0.98). In combination, these data suggested that Lys-PG mediated mechanisms inhibited the membranolytic action of M5-NH against , thereby rendering the organism resistant to the peptide. These results are discussed in relation to structure/function relationships of M5-NH and CM lipids that underpin bacterial susceptibility and resistance to the peptide.
Topics: Staphylococcus aureus; Antimicrobial Cationic Peptides; Cell Membrane; Membrane Lipids; Anti-Bacterial Agents
PubMed: 37869970
DOI: 10.1039/d3sm01007d -
Journal of Neuroendocrinology Nov 2023Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic... (Review)
Review
Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic hypophysiotropic factors, and to the isolation and cloning of multiple brain neuropeptides. These discoveries were followed by the discovery of G-protein-coupled and other membrane receptors for these peptides. Subsequently, the systems physiology associated with some of these multiple regulatory peptides and receptors has been comprehensively elucidated and has led to improved therapeutics and diagnostics and their approval by the US Food and Drug Administration. In light of this wealth of information and further potential, it is truly a time of renaissance for regulatory peptides. In this perspective, we review what we have learned from the pioneers in exemplified fields of gut peptides, such as cholecystokinin, enterochromaffin-like-cell peptides, and glucagon, from the trailblazing studies on the key stress hormone, corticotropin-releasing factor, as well as from more recently characterized relaxin-family peptides and receptors. The historical viewpoints are based on our understanding of these topics in light of the earliest phases of research and on subsequent studies and the evolution of knowledge, aiming to sharpen our vision of the current state-of-the-art and those studies that should be prioritized in the future.
Topics: Neuropeptides; Corticotropin-Releasing Hormone; Cholecystokinin; Relaxin; Glucagon
PubMed: 37053148
DOI: 10.1111/jne.13251 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2023The creation of complementary products via templating is a hallmark feature of nucleic acid replication. Outside of nucleic acid-like molecules, the templated synthesis...
The creation of complementary products via templating is a hallmark feature of nucleic acid replication. Outside of nucleic acid-like molecules, the templated synthesis of a hetero-complementary copy is still rare. Herein we describe one cycle of templated synthesis that creates homomeric macrocyclic peptides guided by linear instructing strands. This strategy utilizes hydrazone formation to pre-organize peptide oligomeric monomers along the template on a solid support resin, and microwave-assisted peptide synthesis to couple monomers and cyclize the strands. With a flexible templating strand, we can alter the size of the complementary macrocycle products by increasing the length and number of the binding peptide oligomers, showing the potential to precisely tune the size of macrocyclic products. For the smaller macrocyclic peptides, the products can be released via hydrolysis and characterized by ESI-MS.
Topics: Peptides; Chemistry Techniques, Synthetic; Nucleic Acids
PubMed: 37475574
DOI: 10.1002/chem.202301949 -
Cancer Research Communications Nov 2023IFNγ alters the immunopeptidome presented on HLA class I (HLA-I), and its activity on cancer cells is known to be important for effective immunotherapy responses. We...
UNLABELLED
IFNγ alters the immunopeptidome presented on HLA class I (HLA-I), and its activity on cancer cells is known to be important for effective immunotherapy responses. We performed proteomic analyses of untreated and IFNγ-treated colorectal cancer patient-derived organoids and combined this with transcriptomic and HLA-I immunopeptidomics data to dissect mechanisms that lead to remodeling of the immunopeptidome through IFNγ. IFNγ-induced changes in the abundance of source proteins, switching from the constitutive to the immunoproteasome, and differential upregulation of different HLA alleles explained some, but not all, observed peptide abundance changes. By selecting for peptides which increased or decreased the most in abundance, but originated from proteins with limited abundance changes, we discovered that the amino acid composition of presented peptides also influences whether a peptide is upregulated or downregulated on HLA-I through IFNγ. The presence of proline within the peptide core was most strongly associated with peptide downregulation. This was validated in an independent dataset. Proline substitution in relevant core positions did not influence the predicted HLA-I binding affinity or stability, indicating that proline effects on peptide processing may be most relevant. Understanding the multiple factors that influence the abundance of peptides presented on HLA-I in the absence or presence of IFNγ is important to identify the best targets for antigen-specific cancer immunotherapies such as vaccines or T-cell receptor engineered therapeutics.
SIGNIFICANCE
IFNγ remodels the HLA-I-presented immunopeptidome. We showed that peptide-specific factors influence whether a peptide is upregulated or downregulated and identified a preferential loss or downregulation of those with proline near the peptide center. This will help selecting immunotherapy target antigens which are consistently presented by cancer cells.
Topics: Humans; Proteomics; Neoplasms; Interferon-gamma; Antigens; Peptides; Proline
PubMed: 37991387
DOI: 10.1158/2767-9764.CRC-23-0121 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2024Thioamides are naturally occurring isosteres of amide bonds in which the chalcogen atom of the carbonyl is changed from oxygen to sulfur. This substitution gives rise to... (Review)
Review
Thioamides are naturally occurring isosteres of amide bonds in which the chalcogen atom of the carbonyl is changed from oxygen to sulfur. This substitution gives rise to altered nucleophilicity and hydrogen bonding properties with importance for both chemical reactivity and non-covalent interactions. As such, thioamides have been introduced into biologically active compounds to achieve improved target affinity and/or stability towards hydrolytic enzymes but have also been applied as probes of protein and peptide folding and dynamics. Recently, a series of new methods have been developed for the synthesis of thioamides as well as their utilization in peptide chemistry. Further, novel strategies for the incorporation of thioamides into proteins have been developed, enabling both structural and functional studies to be performed. In this Review, we highlight the recent developments in the preparation of thioamides and their applications for peptide modification and study of protein function.
Topics: Thioamides; Peptides; Proteins; Amides; Sulfur
PubMed: 38088462
DOI: 10.1002/chem.202303770 -
Biomedicine & Pharmacotherapy =... Sep 2023Na1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively...
Na1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Na1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Na1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.
Topics: Humans; Peptides; Voltage-Gated Sodium Channels; Structure-Activity Relationship
PubMed: 37453200
DOI: 10.1016/j.biopha.2023.115173 -
Proceedings of the National Academy of... Mar 2024Sponges (Porifera) contain many peptide-specialized metabolites with potent biological activities and significant roles in shaping marine ecology. It is well established...
Sponges (Porifera) contain many peptide-specialized metabolites with potent biological activities and significant roles in shaping marine ecology. It is well established that symbiotic bacteria produce bioactive "sponge" peptides, both on the ribosome (RiPPs) and nonribosomally. Here, we demonstrate that sponges themselves also produce many bioactive macrocyclic peptides, such as phakellistatins and related proline-rich macrocyclic peptides (PRMPs). Using the sponge transcriptome, methods were developed to find sequences encoding 46 distinct RiPP-type core peptides, of which ten encoded previously identified PRMP sequences. With this basis set, the genome and transcriptome of the sponge was interrogated to find 35 PRMP precursor peptides encoding 31 unique core peptide sequences. At least 11 of these produced cyclic peptides that were present in the sponge and could be characterized by mass spectrometry, including stylissamides A-D and seven previously undescribed compounds. Precursor peptides were encoded in the genome, confirming their animal origin. The peptides contained signal peptide sequences and highly repetitive recognition sequence-core peptide elements with up to 25 PRMP copies in a single precursor. In comparison to sponges without PRMPs, PRMP sponges are incredibly enriched in potentially secreted polypeptides, with >23,000 individual signal peptide encoding genes found in a single transcriptome. The similarities between PRMP biosynthetic genes and neuropeptides in terms of their biosynthetic logic suggest a fundamental biology linked to circular peptides, possibly indicating a widespread and underappreciated diversity of signaling peptide post-translational modifications across the animal kingdom.
Topics: Animals; Peptides; Peptides, Cyclic; Amino Acid Sequence; Bandages; Protein Sorting Signals
PubMed: 38442178
DOI: 10.1073/pnas.2314383121