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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 -
Toxins Apr 2016Solitary wasps paralyze insects or spiders with stinging venom and feed the paralyzed preys to their larva. Accordingly, the venoms should contain a variety of... (Review)
Review
Solitary wasps paralyze insects or spiders with stinging venom and feed the paralyzed preys to their larva. Accordingly, the venoms should contain a variety of constituents acting on nervous systems. However, only a few solitary wasp venoms have been chemically studied despite thousands of species inhabiting the planet. We have surveyed bioactive substances in solitary wasp venoms found in Japan and discovered a variety of novel bioactive peptides. Pompilidotoxins (PMTXs), in the venoms of the pompilid wasps Anoplius samariensis and Batozonellus maculifrons, are small peptides consisting of 13 amino acids without a disulfide bond. PMTXs slowed Na⁺ channel inactivation, in particular against neuronal type Na⁺ channels, and were rather selective to the Nav1.6 channel. Mastoparan-like cytolytic and antimicrobial peptides are the major components of eumenine wasp venoms. They are rich in hydrophobic and basic amino acids, adopting a α-helical secondary structure, and showing mast cell degranulating, antimicrobial and hemolytic activities. The venom of the spider wasp Cyphononyx fulvognathus contained four bradykinin-related peptides. They are hyperalgesic and, dependent on the structure, differently associated with B₁ or B₂ receptors. Further survey led to the isolation of leucomyosuppressin-like FMRFamide peptides from the venoms of the digger wasps Sphex argentatus and Isodontia harmandi. These results of peptide toxins in solitary wasp venoms from our studies are summarized.
Topics: Animals; Bradykinin; FMRFamide; Humans; Insect Proteins; Peptides; Wasp Venoms
PubMed: 27096870
DOI: 10.3390/toxins8040114 -
Nature Communications Apr 2020Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new...
Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new type of conjugate that consists of a nanobody and a peptidic ligand for a G protein-coupled receptor (GPCR), fused via their C-termini. We address activation of parathyroid hormone receptor-1 (PTHR1) and improve the signaling activity and specificity of otherwise poorly active N-terminal peptide fragments of PTH by conjugating them to nanobodies (VHHs) that recognize PTHR1. These C-to-C conjugates show biological activity superior to that of the parent fragment peptide in vitro. In an exploratory experiment in mice, a VHH-PTH peptide conjugate showed biological activity, whereas the corresponding free peptide did not. The lead conjugate also possesses selectivity for PTHR1 superior to that of PTH(1-34). This design approach, dubbed "conjugation of ligands and antibodies for membrane proteins" (CLAMP), can yield ligands with high potency and specificity.
Topics: Amino Acid Sequence; Animals; Female; HEK293 Cells; Humans; Ligands; Mice; Models, Molecular; Parathyroid Hormone; Peptides; Protein Binding; Receptor, Parathyroid Hormone, Type 1; Receptors, G-Protein-Coupled; Single-Domain Antibodies
PubMed: 32350260
DOI: 10.1038/s41467-020-15884-8 -
International Journal of Molecular... Dec 2022Cytokine imbalance is one of the causes of inflammation. Inflammation has yet to be adequately treated without side effects. Therefore, we tried to develop a peptide...
Cytokine imbalance is one of the causes of inflammation. Inflammation has yet to be adequately treated without side effects. Therefore, we tried to develop a peptide drug with minimal side effects. Peptide drugs have the advantage of being bio-friendly and bio-specific. In a previous study, three peptides with anti-inflammatory activity were derived based on a truncated IK (tIK) protein, which was a fragment of the IK protein with anti-inflammatory effects. The objective of this study was to optimize the process of expressing, isolating, and purifying the three peptides using bacterial strains and describe the process. Circular dichroism and solution state nuclear magnetic resonance spectroscopy were performed on the final purified high-purity peptide and its secondary structure was also identified.
Topics: Humans; Anti-Inflammatory Agents; Peptides; Inflammation; Cytokines; Protein Structure, Secondary; Circular Dichroism
PubMed: 36614076
DOI: 10.3390/ijms24010636 -
Biochemical Society Transactions Oct 2020The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as... (Review)
Review
The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as hydrogen bridges or is induced by ligand-receptor interactions. The conformational freedom of a peptide can be constrained by intramolecular cross-links. Conformational constraints enhance the receptor specificity, may lead to biased activity and confer proteolytic resistance to peptidic GPCR agonists. Chemical synthesis allows to introduce a variety of cross-links into a peptide and is suitable for bulk production of relatively simple lead peptides. Lanthionines are thioether bridged alanines of which the two alanines can be introduced at different distances in chosen positions in a peptide. Thioether bridges are much more stable than disulfide bridges. Biosynthesis of lanthionine-constrained peptides exploiting engineered Gram-positive or Gram-negative bacteria that contain lanthionine-introducing enzymes constitutes a convenient method for discovery of lanthionine-stabilized GPCR agonists. The presence of an N-terminal leader peptide enables dehydratases to dehydrate serines and threonines in the peptide of interest after which a cyclase can couple the formed dehydroamino acids to cysteines forming (methyl)lanthionines. The leader peptide also guides the export of the formed lanthionine-containing precursor peptide out of Gram-positive bacteria via a lanthipeptide transporter. An engineered cleavage site in the C-terminus of the leader peptide allows to cleave off the leader peptide yielding the modified peptide of interest. Lanthipeptide GPCR agonists are an emerging class of therapeutics of which a few examples have demonstrated high efficacy in animal models of a variety of diseases. One lanthipeptide GPCR agonist has successfully passed clinical Phase Ia.
Topics: Alanine; Animals; Anti-Bacterial Agents; Bacterial Proteins; Disulfides; Drug Discovery; GTP-Binding Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Lanthanoid Series Elements; Membrane Transport Proteins; Mice; Peptide Hydrolases; Peptides; Protein Domains; Protein Processing, Post-Translational; Protein Sorting Signals; Rats; Receptors, G-Protein-Coupled; Substrate Specificity; Sulfides
PubMed: 33125486
DOI: 10.1042/BST20200427 -
International Journal of Molecular... Jul 2023Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is... (Review)
Review
Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood-brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones' levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide's actions to improve symptoms and the progression of several pathologies.
Topics: Animals; Humans; Thyrotropin-Releasing Hormone; Brain; Thyroid Gland; Peptides; Thyroid Hormones
PubMed: 37446225
DOI: 10.3390/ijms241311047 -
Biological Chemistry Dec 2019Proteases are regulators of diverse biological pathways including protein catabolism, antigen processing and inflammation, as well as various disease conditions, such as... (Review)
Review
Proteases are regulators of diverse biological pathways including protein catabolism, antigen processing and inflammation, as well as various disease conditions, such as malignant metastasis, viral infection and parasite invasion. The identification of substrates of a given protease is essential to understand its function and this information can also aid in the design of specific inhibitors and active site probes. However, the diversity of putative protein and peptide substrates makes connecting a protease to its downstream substrates technically difficult and time-consuming. To address this challenge in protease research, a range of methods have been developed to identify natural protein substrates as well as map the overall substrate specificity patterns of proteases. In this review, we highlight recent examples of both synthetic and biological methods that are being used to define the substrate specificity of protease so that new protease-specific tools and therapeutic agents can be developed.
Topics: Humans; Peptide Hydrolases; Peptides; Protease Inhibitors; Signal Transduction; Substrate Specificity
PubMed: 31639098
DOI: 10.1515/hsz-2019-0332 -
Molecules (Basel, Switzerland) May 2019In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy... (Review)
Review
In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.
Topics: Animals; Body Weight; Cardiovascular System; Cyclic AMP; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Kinetics; Ligands; Peptides; Primates; Protein Binding; Protein Transport; Receptor, Melanocortin, Type 4; Rodentia; Signal Transduction; alpha-MSH
PubMed: 31100979
DOI: 10.3390/molecules24101892 -
Small Peptides in the Detection of Mycotoxins and Their Potential Applications in Mycotoxin Removal.Toxins Nov 2022Mycotoxins pose significant risks to humans and livestock. In addition, contaminated food- and feedstuffs can only be discarded, leading to increased economic losses and... (Review)
Review
Mycotoxins pose significant risks to humans and livestock. In addition, contaminated food- and feedstuffs can only be discarded, leading to increased economic losses and potential ecological pollution. Mycotoxin removal and real-time toxin level monitoring are effective approaches to solve this problem. As a hot research hotspot, small peptides derived from phage display peptide libraries, combinatorial peptide libraries, and rational design approaches can act as coating antigens, competitive antigens, and anti-immune complexes in immunoassays for the detection of mycotoxins. Furthermore, as a potential approach to mycotoxin degradation, small peptides can mimic the natural enzyme catalytic site to construct artificial enzymes containing oxidoreductases, hydrolase, and lyase activities. In summary, with the advantages of mature synthesis protocols, diverse structures, and excellent biocompatibility, also sharing their chemical structure with natural proteins, small peptides are widely used for mycotoxin detection and artificial enzyme construction, which have promising applications in mycotoxin degradation. This paper mainly reviews the advances of small peptides in the detection of mycotoxins, the construction of peptide-based artificial enzymes, and their potential applications in mycotoxin control.
Topics: Immunoassay; Mycotoxins; Peptide Library; Peptides
PubMed: 36422969
DOI: 10.3390/toxins14110795 -
Genes May 2023Leveraging computation in the development of peptide therapeutics has garnered increasing recognition as a valuable tool to generate novel therapeutics for... (Review)
Review
Leveraging computation in the development of peptide therapeutics has garnered increasing recognition as a valuable tool to generate novel therapeutics for disease-related targets. To this end, computation has transformed the field of peptide design through identifying novel therapeutics that exhibit enhanced pharmacokinetic properties and reduced toxicity. The process of peptide design involves the application of molecular docking, molecular dynamics simulations, and machine learning algorithms. Three primary approaches for peptide therapeutic design including structural-based, protein mimicry, and short motif design have been predominantly adopted. Despite the ongoing progress made in this field, there are still significant challenges pertaining to peptide design including: enhancing the accuracy of computational methods; improving the success rate of preclinical and clinical trials; and developing better strategies to predict pharmacokinetics and toxicity. In this review, we discuss past and present research pertaining to the design and development of peptide therapeutics in addition to highlighting the potential of computation and artificial intelligence in the future of disease therapeutics.
Topics: Animals; Artificial Intelligence; Molecular Docking Simulation; Feathers; Peptides; Proteins
PubMed: 37372372
DOI: 10.3390/genes14061194