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Current Drug Metabolism 2018Despite the therapeutic use of peptides is limited because of their metabolism in vivo, there are no systematic reviews explaining degradation of peptides by peptidases.... (Review)
Review
BACKGROUND
Despite the therapeutic use of peptides is limited because of their metabolism in vivo, there are no systematic reviews explaining degradation of peptides by peptidases. This review summarizes peptidases present in the tissues and metabolic characteristics of peptides, and provides recent strategies for improving the metabolic stability of peptides.
METHOD
We reviewed a number of peptidases including their functional groups, tissue localization and cleavage specificity. Given the broad distribution of peptidases in the body, several tissues, such as the liver, kidney, lung, blood, nasal epithelial cells, placenta and skin, have the capacity to metabolize peptides. We compared the metabolic characteristics of peptides in these tissues and then summarized strategies for improving peptide stability.
RESULTS
In addition to the primary organs including liver, kidney, gastrointestinal tract and blood involved in peptide metabolism, other organs such as the lung, skin, placenta and nasal mucosa may also play a role in peptide degradation. At present, the main measures to improve the stability of the peptide include N- and/or C-terminal modification or substitution, D-amino acid or unnatural amino acid substitution, cyclization, backbone modification, nanoparticle formulations and increased molecular mass.
CONCLUSION
This review summarized the key in vivo peptidases and their tissue distribution characteristics, and presented strategies to improve the metabolic stability and bioavailability of peptide drugs. These viewpoints will benefit the further development and utilization of peptide drugs.
Topics: Animals; Humans; Peptide Hydrolases; Peptides; Proteolysis; Tissue Distribution
PubMed: 29956618
DOI: 10.2174/1389200219666180628171531 -
Angewandte Chemie (International Ed. in... Mar 2017Nonribosomal peptide synthetases (NRPSs) are large multienzyme machineries that assemble numerous peptides with large structural and functional diversity. These peptides... (Review)
Review
Nonribosomal peptide synthetases (NRPSs) are large multienzyme machineries that assemble numerous peptides with large structural and functional diversity. These peptides include more than 20 marketed drugs, such as antibacterials (penicillin, vancomycin), antitumor compounds (bleomycin), and immunosuppressants (cyclosporine). Over the past few decades biochemical and structural biology studies have gained mechanistic insights into the highly complex assembly line of nonribosomal peptides. This Review provides state-of-the-art knowledge on the underlying mechanisms of NRPSs and the variety of their products along with detailed analysis of the challenges for future reprogrammed biosynthesis. Such a reprogramming of NRPSs would immediately spur chances to generate analogues of existing drugs or new compound libraries of otherwise nearly inaccessible compound structures.
Topics: Peptide Biosynthesis, Nucleic Acid-Independent; Peptide Synthases; Peptides
PubMed: 28323366
DOI: 10.1002/anie.201609079 -
Cell Metabolism Sep 2019Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using...
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interferon-gamma; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Microglia; Oxidative Phosphorylation; Phagocytosis; Recombinant Proteins; TOR Serine-Threonine Kinases
PubMed: 31257151
DOI: 10.1016/j.cmet.2019.06.005 -
Journal of Peptide Science : An... Jan 2016Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale... (Review)
Review
Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications.
Topics: Amino Acids; Aspartic Acid; Cell Line; Epithelial Cells; Fluorenes; Glycosylation; Humans; Methylation; Peptides; Phosphorylation; Protein Prenylation; Protein Processing, Post-Translational; Solid-Phase Synthesis Techniques
PubMed: 26785684
DOI: 10.1002/psc.2836 -
Journal of Controlled Release :... Oct 2020Exosomes are natural nanovesicles excreted by many cells for intercellular communication and for transfer of materials including proteins, nucleic acids and even... (Review)
Review
Exosomes are natural nanovesicles excreted by many cells for intercellular communication and for transfer of materials including proteins, nucleic acids and even synthetic therapeutic agents. Surface modification of exosomes imparts additional functionality to the exosomes to enable site specific drug delivery and in vivo imaging and tracking and is an emerging area in drug delivery research. The present review focuses upon these modifications on the exosomal surface, the chemistry involved and their impact on targeted drug delivery for the treatment of brain, breast, lung, liver, colon tumors and, heart diseases and for understanding their in vivo fate including their uptake mechanisms, pharmacokinetics and biodistribution. The specific exosomal membrane proteins such as tetraspanins (CD63, CD81, CD9), lactadherin (LA), lysosome associated membrane protein-2b (Lamp-2b) and, glycosyl-phosphatidyl-inositol (GPI) involved in functionalization of exosome surface have also been discussed along with different strategies of surface modification like genetic engineering, covalent modification (click chemistry and metabolic engineering of parent cells of exosomes) and non-covalent modification (multivalent electrostatic interactions, ligand-receptor interaction, hydrophobic interaction, aptamer based modification and modification by anchoring CP05 peptide) along with optical (fluorescent and bioluminescent) and radioactive isotope labelling techniques of exosomes for imaging purpose.
Topics: Drug Delivery Systems; Exosomes; Peptides; Proteins; Tissue Distribution
PubMed: 32730952
DOI: 10.1016/j.jconrel.2020.07.042 -
Nutrients Jun 2020Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white... (Review)
Review
The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review.
Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body's response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.
Topics: Adipokines; Adipose Tissue; Animals; Appetite Regulation; Body Composition; Bone and Bones; Energy Metabolism; Exercise; Humans; Lipid Metabolism; Liver; Metabolic Networks and Pathways; Muscle, Skeletal; Obesity; Peptide Hormones; Peptides; Weight Loss
PubMed: 32604889
DOI: 10.3390/nu12061899 -
Angewandte Chemie (International Ed. in... Sep 2023Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte...
Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte growth factor (HGF) receptor, known as MET, plays an important role in tissue regeneration. Here we show the development of ubiquitin (Ub)-based protein ligand multimers, referred to as U-bodies, which act as surrogate agonists for MET and are derived from MET-binding macrocyclic peptides. Monomeric Ub constructs (U-body) were first generated by genetic implantation of a macrocyclic peptide pharmacophore into a structural loop of Ub (lasso-grafting) and subsequent optimization of its flanking spacer sequences via mRNA display. Such U-body constructs exhibit potent binding affinity to MET, thermal stability, and proteolytic stability. The U-body constructs also partially/fully inhibited or enhanced HGF-induced MET-phosphorylation. Their multimerization to dimeric, tetrameric, and octameric U-bodies linked by an appropriate peptide linker yielded potent MET activation activity and downstream cell proliferation-promoting activity. This work suggests that lasso-grafting of macrocycles to Ub is an effective approach to devising protein-based artificial RTK agonists and it can be useful in the development of a new class of biologics for various therapeutic applications.
Topics: Hepatocyte Growth Factor; Ubiquitin; Protein Binding; Proto-Oncogene Proteins c-met; Phosphorylation; Peptides
PubMed: 37450419
DOI: 10.1002/anie.202307157 -
Chemical Reviews Mar 2020Subtiligase-catalyzed peptide ligation is a powerful approach for site-specific protein bioconjugation, synthesis and semisynthesis of proteins and peptides, and... (Review)
Review
Subtiligase-catalyzed peptide ligation is a powerful approach for site-specific protein bioconjugation, synthesis and semisynthesis of proteins and peptides, and chemoproteomic analysis of cellular N termini. Here, we provide a comprehensive review of the subtiligase technology, including its development, applications, and impacts on protein science. We highlight key advantages and limitations of the tool and compare it to other peptide ligase enzymes. Finally, we provide a perspective on future applications and challenges and how they may be addressed.
Topics: Biocatalysis; Peptide Synthases; Peptides; Subtilisins
PubMed: 31663725
DOI: 10.1021/acs.chemrev.9b00372 -
Natural Product Reports Sep 2020Covering1993 up to May 2020 Linaridins, defined as linear, dehydrated (arid) peptides, are a small but growing family of natural products belonging to the ribosomally... (Review)
Review
Covering1993 up to May 2020 Linaridins, defined as linear, dehydrated (arid) peptides, are a small but growing family of natural products belonging to the ribosomally synthesized and post-translationally modified peptide (RiPP) superfamily. To date, only a few members of the linaridin family have been characterized; however, in silico analysis has shown that this family of RiPPs is widespread in nature with high structural diversity. Unlike the case of most of the dehydroamino acid-containing RiPPs, such as lanthipeptides and thiopeptides, in which dehydroamino acids are produced by lanthipeptide dehydratase-like enzymes, in linaridins, dehydroamino acids are produced by a distinct set of enzymes with still unknown biochemistry. In this Highlight we have discussed the structural features, classification, biosynthesis, engineering, and widespread occurrence of linaridins and highlighted several intriguing issues in the maturation of this RiPP family.
Topics: Bioengineering; Biological Products; Peptide Biosynthesis; Peptides; Protein Processing, Post-Translational; Terminology as Topic
PubMed: 32484193
DOI: 10.1039/c9np00074g -
Molecular & Cellular Proteomics : MCP Jul 2020Protein-protein interactions are often mediated by short linear motifs (SLiMs) that are located in intrinsically disordered regions (IDRs) of proteins. Interactions... (Review)
Review
Protein-protein interactions are often mediated by short linear motifs (SLiMs) that are located in intrinsically disordered regions (IDRs) of proteins. Interactions mediated by SLiMs are notoriously difficult to study, and many functionally relevant interactions likely remain to be uncovered. Recently, pull-downs with synthetic peptides in combination with quantitative mass spectrometry emerged as a powerful screening approach to study protein-protein interactions mediated by SLiMs. Specifically, arrays of synthetic peptides immobilized on cellulose membranes provide a scalable means to identify the interaction partners of many peptides in parallel. In this minireview we briefly highlight the relevance of SLiMs for protein-protein interactions, outline existing screening technologies, discuss unique advantages of peptide-based interaction screens and provide practical suggestions for setting up such peptide-based screens.
Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Computational Biology; Humans; Mass Spectrometry; Mice; Peptides; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Proteins; Proteomics
PubMed: 32345597
DOI: 10.1074/mcp.R120.002034