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Advances in Experimental Medicine and... 2020Peptides, as a large group of molecules, are composed of amino acid residues and can be divided into linear or cyclic peptides according to the structure. Over 13,000... (Review)
Review
Peptides, as a large group of molecules, are composed of amino acid residues and can be divided into linear or cyclic peptides according to the structure. Over 13,000 molecules of natural peptides have been found and many of them have been well studied. In artificial peptide libraries, the number of peptide diversity could be up to 1 × 10. Peptides have more complex structures and higher affinity to target proteins comparing with small molecular compounds. Recently, the development of targeting cancer immune checkpoint (CIP) inhibitors is having a very important role in tumor therapy. Peptides targeting ligands or receptors in CIP have been designed based on three-dimensional structures of target proteins or directly selected by random peptide libraries in biological display systems. Most of these targeting peptides work as inhibitors of protein-protein interaction and improve CD8+ cytotoxic T-lymphocyte (CTL) activation in the tumor microenvironment, for example, PKHB1, Ar5Y4 and TPP1. Peptides could be designed to regulate CIP protein degradation in vivo, such as PD-LYSO and PD-PALM. Besides its use in developing therapeutic drugs for targeting CIP, targeting peptides could be used in drug's targeted delivery and diagnosis in tumor immune therapy.
Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Drug Delivery Systems; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Peptide Library; Peptides; Tripeptidyl-Peptidase 1
PubMed: 32185724
DOI: 10.1007/978-981-15-3266-5_21 -
Protein and Peptide Letters 2022Gut peptides are small peptides secreted by gut endocrine cells that can modulate the roles and functions of different organs through signaling. Gut peptides can also... (Review)
Review
Gut peptides are small peptides secreted by gut endocrine cells that can modulate the roles and functions of different organs through signaling. Gut peptides can also majorly impact the body's energy homeostasis by regulating appetite and energy metabolism. The gut-brain axis (GBA) is bidirectional communication between the central nervous system (CNS) and the peripheral enteric nervous system. The regulation of appetite acts by hypothalamic neuronal activity. The complex interaction of hedonic and homeostatic factors implicates appetite regulation. In the CNS, the hypothalamus and brainstem have a dominating role in appetite regulation. The arcuate nucleus (ARC) of the hypothalamus plays a vital role in energy homeostasis, while other nuclei also play a role in appetite regulation. The gut conveys peripheral information about energy balance to the brain via gut peptides and receptors for the digestion of food. The varied gut peptides have different actions on appetite regulation.
Topics: Appetite Regulation; Brain; Energy Metabolism; Hypothalamus; Peptides
PubMed: 36125839
DOI: 10.2174/0929866529666220920150127 -
Chemical Reviews Sep 2019Cyclization is an important post-translational modification of peptides and proteins that confers key advantages such as protection from proteolytic degradation, altered... (Review)
Review
Cyclization is an important post-translational modification of peptides and proteins that confers key advantages such as protection from proteolytic degradation, altered solubility, membrane permeability, bioavailability, and especially restricted conformational freedom in water that allows the peptide backbone to adopt the major secondary structure elements found in proteins. Non-ribosomal synthesis in bacteria, fungi, and plants or synthetic chemistry can introduce unnatural amino acids and non-peptidic constraints that modify peptide backbones and side chains to fine-tune cyclic peptide structure. Structures can be potentially altered further upon binding to a protein in biological environments. Here we analyze three-dimensional crystal structures for 211 bioactive cyclic peptides bound to 65 different proteins. The protein-bound cyclic peptides were examined for similarities and differences in bonding modes, for main-chain and side-chain structure, and for the importance of polarity, hydrogen bonds, hydrophobic effects, and water molecules in interactions with proteins. Many protein-bound cyclic peptides show backbone structures like those (strands, sheets, turns, helices, loops, or distorted variations) found at protein-protein binding interfaces. However, the notion of macrocycles simply as privileged scaffolds that primarily project side-chain substituents for complementary interactions with proteins is dispelled here. Unlike small-molecule drugs, the cyclic peptides do not rely mainly upon hydrophobic and van der Waals interactions for protein binding; they also use their main chain and side chains to form polar contacts and hydrogen bonds with proteins. Compared to small-molecule ligands, cyclic peptides can bind across larger, polar, and water-exposed protein surface areas, making many more contacts that can increase affinity, selectivity, biological activity, and ligand-receptor residence time. Cyclic peptides have a greater capacity than small-molecule drugs to modulate protein-protein interfaces that involve large, shallow, dynamic, polar, and water-exposed protein surfaces.
Topics: Animals; Bacteria; Catalytic Domain; Crystallography, X-Ray; Humans; Hydrogen Bonding; Peptides, Cyclic; Protein Binding; Proteins; Static Electricity
PubMed: 31046237
DOI: 10.1021/acs.chemrev.8b00807 -
Annual Review of Biochemistry Jun 2022The past decade has seen impressive advances in understanding the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs). One of the... (Review)
Review
The past decade has seen impressive advances in understanding the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs). One of the most common modifications found in these natural products is macrocyclization, a strategy also used by medicinal chemists to improve metabolic stability and target affinity and specificity. Another tool of the peptide chemist, modification of the amides in a peptide backbone, has also been observed in RiPPs. This review discusses the molecular mechanisms of biosynthesis of a subset of macrocyclic RiPP families, chosen because of the unusual biochemistry involved: the five classes of lanthipeptides (thioether cyclization by Michael-type addition), sactipeptides and ranthipeptides (thioether cyclization by radical chemistry), thiopeptides (cyclization by [4+2] cycloaddition), and streptide (cyclization by radical C-C bond formation). In addition, the mechanisms of backbone amide methylation, backbone epimerization, and backbone thioamide formation are discussed, as well as an unusual route to small molecules by posttranslational modification.
Topics: Amino Acid Sequence; Humans; Peptides; Protein Processing, Post-Translational; Sulfides
PubMed: 35303785
DOI: 10.1146/annurev-biochem-032620-104956 -
Angewandte Chemie (International Ed. in... Jan 2024Proteolysis targeting chimera (PROTAC) is a state-of-the-art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD)... (Review)
Review
Proteolysis targeting chimera (PROTAC) is a state-of-the-art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril-based PROTAC strategy to form a polynary (E3) : PROTAC : (POI) complex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self-assembly-driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so-called Nano-PROTAC provides a novel approach for TPD in cancer therapy.
Topics: Proteolysis; Ligands; Ubiquitin-Protein Ligases; Peptides
PubMed: 38059785
DOI: 10.1002/anie.202316581 -
American Journal of Physiology.... Oct 2020Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have... (Review)
Review
Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metaboloprotective properties. The 12S ribosomal RNA () gene harbors the sequence for MOTS-c, whereas the other seven MDPs [humanin and small humanin-like peptides (SHLP) 1-6] are encoded by the 16S ribosomal RNA gene. Here, we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs, whereas in humans muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c, and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Furthermore, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metaboloprotective properties of MDPs can be harnessed into therapies for metabolic disease.
Topics: Animals; Energy Metabolism; Humans; Mitochondria; Mitochondrial Proteins; Peptides
PubMed: 32776825
DOI: 10.1152/ajpendo.00249.2020 -
Advanced Drug Delivery Reviews Dec 2023Transdermal drug delivery presents a less invasive pathway, circumventing the need to pass through the gastrointestinal tract and liver, thereby reducing drug breakdown,... (Review)
Review
Transdermal drug delivery presents a less invasive pathway, circumventing the need to pass through the gastrointestinal tract and liver, thereby reducing drug breakdown, initial metabolism, and gastrointestinal discomfort. Nevertheless, the unique composition and dense structure of the stratum corneum present a significant barrier to transdermal delivery. This article presents an overview of the current developments in peptides and nanotechnology to address this challenge. Initially, we sum up peptide-containing nanoformulations for transdermal drug delivery, examining them through the lenses of both inorganic and organic materials. Particular emphasis is placed on the diverse roles that peptides play within these nanoformulations, including conferring functionality upon nanocarriers and enhancing the biological efficacy of drugs. Subsequently, we summarize innovative strategies for enhancing skin penetration, categorizing them into passive and active approaches. Lastly, we discuss the therapeutic potential of peptide-containing nanoformulations in addressing a range of diseases, drawing insights from the biological activities and functions of peptides. Furthermore, the challenges hindering clinical translation are also discussed, providing valuable insights for future advancements in transdermal drug delivery.
Topics: Humans; Skin Absorption; Drug Delivery Systems; Skin; Administration, Cutaneous; Peptides
PubMed: 37951358
DOI: 10.1016/j.addr.2023.115139 -
Nature Apr 2023General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, designing...
General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, designing peptide-binding proteins is challenging, as most peptides do not have defined structures in isolation, and hydrogen bonds must be made to the buried polar groups in the peptide backbone. Here, inspired by natural and re-engineered protein-peptide systems, we set out to design proteins made out of repeating units that bind peptides with repeating sequences, with a one-to-one correspondence between the repeat units of the protein and those of the peptide. We use geometric hashing to identify protein backbones and peptide-docking arrangements that are compatible with bidentate hydrogen bonds between the side chains of the protein and the peptide backbone. The remainder of the protein sequence is then optimized for folding and peptide binding. We design repeat proteins to bind to six different tripeptide-repeat sequences in polyproline II conformations. The proteins are hyperstable and bind to four to six tandem repeats of their tripeptide targets with nanomolar to picomolar affinities in vitro and in living cells. Crystal structures reveal repeating interactions between protein and peptide interactions as designed, including ladders of hydrogen bonds from protein side chains to peptide backbones. By redesigning the binding interfaces of individual repeat units, specificity can be achieved for non-repeating peptide sequences and for disordered regions of native proteins.
Topics: Amino Acid Sequence; Models, Molecular; Peptides; Proteins; Protein Engineering; Hydrogen Bonding; Protein Binding; Protein Folding; Protein Conformation
PubMed: 37020023
DOI: 10.1038/s41586-023-05909-9 -
ACS Chemical Biology Jul 2023Disulfide bonds form covalent bonds between distal regions of peptides and proteins to dramatically impact their folding, stability, and oligomerization. Given the...
Disulfide bonds form covalent bonds between distal regions of peptides and proteins to dramatically impact their folding, stability, and oligomerization. Given the prevalence of disulfide bonds in many natural products, considerable effort has been invested in site-selective disulfide bond formation approaches to control the folding of chemically synthesized peptides and proteins. Here, we show that the careful choice of thiol oxidation conditions can lead to monomeric or dimeric species from fully deprotected linear bisthiol peptides. Starting from a p53-derived peptide, we found that oxidation under aqueous (nondenaturing) conditions produces antiparallel dimers with enhanced α-helical character, while oxidation under denaturing conditions promotes formation of a nonhelical intramolecular disulfide species. Examination across peptide variants suggests that intramolecular disulfide formation is robust across diverse peptide sequences, while dimerization is sensitive to both the α-helical folding of the linear peptide and aromatic residues at the dimerization interface. All disulfide species are more resistant to protease degradation than the linear peptide but are easily reduced to restore the initial bisthiol peptide. Both disulfide formation approaches are compatible with α-helix-stabilizing cross-linkers. These results provide an approach for using disulfide bonds to control peptide folding and oligomerization to better understand how folding influences interactions with diverse molecular targets.
Topics: Disulfides; Protein Folding; Dimerization; Proteins; Peptides; Oxidation-Reduction
PubMed: 37390465
DOI: 10.1021/acschembio.3c00268 -
Biomolecules Jan 2021Since the isolation and commercialization of insulin (a peptide composed of 51 amino acid residues) in the early 1920s, peptide drugs have reshaped the pharmaceutical...
Since the isolation and commercialization of insulin (a peptide composed of 51 amino acid residues) in the early 1920s, peptide drugs have reshaped the pharmaceutical industry [...].
Topics: Animals; Biotechnology; Fermentation; Genomics; Humans; Nanotechnology; Peptide Hydrolases; Peptides
PubMed: 33401441
DOI: 10.3390/biom11010052