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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 -
Cold Spring Harbor Protocols Feb 2012The need for reliable, multicistronic vectors for multigene delivery is at the forefront of biomedical technology. This article describes the design and construction of...
The need for reliable, multicistronic vectors for multigene delivery is at the forefront of biomedical technology. This article describes the design and construction of 2A peptide-linked multicistronic vectors, which can be used to express multiple proteins from a single open reading frame (ORF). The small 2A peptide sequences, when cloned between genes, allow for efficient, stoichiometric production of discrete protein products within a single vector through a novel "cleavage" event within the 2A peptide sequence. Expression of more than two genes using conventional approaches has several limitations, most notably imbalanced protein expression and large size. The use of 2A peptide sequences alleviates these concerns. They are small (18-22 amino acids) and have divergent amino-terminal sequences, which minimizes the chance for homologous recombination and allows for multiple, different 2A peptide sequences to be used within a single vector. Importantly, separation of genes placed between 2A peptide sequences is nearly 100%, which allows for stoichiometric and concordant expression of the genes, regardless of the order of placement within the vector.
Topics: Gene Expression; Genes; Genetic Vectors; Open Reading Frames; Peptides; Protein Biosynthesis; Protein Processing, Post-Translational; Proteolysis; Ribosomes
PubMed: 22301656
DOI: 10.1101/pdb.ip067876 -
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 -
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 -
Current Opinion in Structural Biology Apr 2018Nonribosomal peptide synthetases (NRPSs) produce peptide products with wide-ranging biological activities. NRPSs are macromolecular machines with modular assembly-line... (Review)
Review
Nonribosomal peptide synthetases (NRPSs) produce peptide products with wide-ranging biological activities. NRPSs are macromolecular machines with modular assembly-line logic, a complex catalytic cycle, moving parts and multiple active sites. They are organized into repeating sets of domains, called modules. Each module contains all functionality to introduce a building block into the growing peptide, many also perform cosynthetic tailoring. Structures of individual domains have provided insights into their catalytic mechanisms, but with one exception, larger NRPS proteins were refractory to structure determination. Recently, structure determination succeeded for four multi-domain NRPS proteins: an alternative formylating initiation and two termination modules as well as a large cross-module construct. This review highlights how these data, together with novel didomain structures, contribute to a holistic view of the architecture, domain-domain interactions and conformational changes in NRPS megaenzymes.
Topics: Catalytic Domain; Models, Molecular; Molecular Conformation; Peptide Biosynthesis, Nucleic Acid-Independent; Peptide Synthases; Peptides; Protein Binding; Structure-Activity Relationship
PubMed: 29444491
DOI: 10.1016/j.sbi.2018.01.011 -
Peptides Apr 2016Peptide YY 3-36-amide (PYY3-36) is a peptide hormone, which is known to decrease appetite and food-intake by activation of the Y2 receptor. The current studies were...
Peptide YY 3-36-amide (PYY3-36) is a peptide hormone, which is known to decrease appetite and food-intake by activation of the Y2 receptor. The current studies were designed to identify the metabolites of PYY3-36 in mini-pig and rhesus monkey. Plasma samples were analyzed by high resolution LC-MS (and MS/MS) in order to unambiguously identify the metabolites of PYY3-36. In summary, the metabolism of PYY3-36 was similar in mini-pig and rhesus monkey. Several metabolites were identified and PYY3-34 was identified at the highest levels in plasma. In addition, mini-pigs were also dosed with PYY1-36-amide, PYY3-35, PYY3-34 and [N-methyl 34Q]-PYY3-36-amide in order to investigate the mechanisms by which PYY was metabolized. PYY3-35 was rapidly converted to PYY3-34 whereas dosing of PYY3-34 to mini-pigs only showed circulating degradation products at low levels, i.e., PYY3-34 was metabolically more stable than PYY3-36 and PYY3-35. [N-methyl 34Q]-PYY3-36-amide was hypothesized to be stable toward cleavage between 34Q and 35R and after i.v. administration to mini-pigs, one major cleavage product was identified as [N-methyl 34Q]-PYY3-35. Overall, this showed that cleavage between 35R and 36Y was possible as well as between 34Q and 35R (as shown for PYY3-35), which indicated that metabolism of PYY3-36 to PYY3-34 may be a two-step process. PYY1-36 was also dosed to mini-pigs, which showed that PYY1-36 was metabolized in the C-terminal as PYY3-36. The overall degradation pattern of PYY1-36 was more complex due to the simultaneous enzymatic degradation in the N-terminal to form PYY2-34/36 and PYY3-34/36. In vitro incubations with heparin stabilized plasma showed that PYY3-36 was degraded with a half-life of 175 min, whereas incubations with PYY3-35 (half-life of 6 min) showed a rapid formation of PYY3-34. In conclusion, the present studies showed that PYY3-36 underwent enzymatic degradation in the C-terminal part and that the major circulating metabolite was PYY3-34. Furthermore, it may be a sequential two-step process leading to the formation of PYY3-35 and subsequently the metabolically more stable PYY3-34.
Topics: Animals; Appetite; Biotransformation; Chromatography, Liquid; Eating; Female; Half-Life; Macaca mulatta; Male; Peptide Fragments; Peptide YY; Proteolysis; Receptors, Neuropeptide Y; Swine; Swine, Miniature; Tandem Mass Spectrometry
PubMed: 26774588
DOI: 10.1016/j.peptides.2016.01.010 -
Methods in Molecular Biology (Clifton,... 2012Peptide-protein interactions are prevalent in the living cell and form a key component of the overall protein-protein interaction network. These interactions are drawing...
Peptide-protein interactions are prevalent in the living cell and form a key component of the overall protein-protein interaction network. These interactions are drawing increasing interest due to their part in signaling and regulation, and are thus attractive targets for computational structural modeling. Here we report an overview of current techniques for the high resolution modeling of peptide-protein complexes. We dissect this complicated challenge into several smaller subproblems, namely: modeling the receptor protein, predicting the peptide binding site, sampling an initial peptide backbone conformation and the final refinement of the peptide within the receptor binding site. For each of these conceptual stages, we present available tools, approaches, and their reported performance. We summarize with an illustrative example of this process, highlighting the success and current challenges still facing the automated blind modeling of peptide-protein interactions. We believe that the upcoming years will see considerable progress in our ability to create accurate models of peptide-protein interactions, with applications in binding-specificity prediction, rational design of peptide-mediated interactions and the usage of peptides as therapeutic agents.
Topics: Binding Sites; Databases, Protein; Models, Molecular; Peptides; Protein Binding; Protein Interaction Mapping; Protein Interaction Maps; Proteins; Software
PubMed: 22323231
DOI: 10.1007/978-1-61779-588-6_17 -
Xenobiotica; the Fate of Foreign... Apr 2023Challenges within peptide and oligonucleotide ADME (absorption, distribution, metabolism and elimination) and scientific ideas on how to solve them were presented and... (Review)
Review
Challenges within peptide and oligonucleotide ADME (absorption, distribution, metabolism and elimination) and scientific ideas on how to solve them were presented and discussed at the DMDG (Drug Metabolism and Discussion Group) Peptide and Oligonucleotide ADME Workshop 2022 (2nd and 3rd of October 2022). This meeting report summarises the presentations and discussions from this workshop.The following topics were covered:Overview of the drug modality landscapeMetabolism & modellingAnalytical challengesDrug-drug interactions reports from industry working groupsRegulatory interactions.
Topics: Peptides; Drug Interactions; Metabolic Clearance Rate
PubMed: 37309582
DOI: 10.1080/00498254.2023.2223666 -
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