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Chemical & Pharmaceutical Bulletin 2021Non-canonical amino acid derivatives are an attractive scaffold for novel drug candidates. Among the methods used to prepare this motif, the asymmetric Mannich-type... (Review)
Review
Non-canonical amino acid derivatives are an attractive scaffold for novel drug candidates. Among the methods used to prepare this motif, the asymmetric Mannich-type reaction of α-imino carboxylic acid derivatives is a preeminent strategy because a wide variety of non-canonical amino acids can be accessed by changing only the nucleophile. Preparing the common substrate is difficult, however, which makes this method problematic. We developed a convenient method for synthesizing common substrates using MnO-mediated oxidation of stable precursors. Peptides bearing non-canonical amino acids are another attractive synthetic target. We propose a new approach for synthesizing non-canonical amino acid-containing peptides by directly applying various organic reactions to peptidic substrates. Using hydrophobic anchor-supported peptides, we directly applied ring-closing metathesis and asymmetric Friedel-Crafts reactions to peptidic substrates. We also developed a novel recyclable organocatalyst according to the nature of the hydrophobic anchor tagged compound.
Topics: Amino Acids; Catalysis; Chemistry Techniques, Synthetic; Drug Discovery; Manganese Compounds; Oxidation-Reduction; Oxides; Peptides; Pharmaceutical Preparations
PubMed: 33790076
DOI: 10.1248/cpb.c21-00031 -
Current Pharmaceutical Design 2010Functions and properties of native peptides vary from highly specific antibiotics or cytotoxic antitumor drugs, to hormones, neurotransmitters, immunomodulators, etc.... (Review)
Review
Functions and properties of native peptides vary from highly specific antibiotics or cytotoxic antitumor drugs, to hormones, neurotransmitters, immunomodulators, etc. Despite their potential utility as therapeutic agents, there are problems connected with the use of natural peptides, due to the low stability against proteolysis, resulting in a short duration of in vivo activity, and in a low bioavailability. One way to overcome these disadvantages is the use of modified peptides, the so called peptidomimetics. Overall, the less peptide character in a drug candidate, the more stable it is towards protease cleavage. A huge number of non-peptidic scaffolds have been reported in the literature; nevertheless, several cases have failed to reproduce the activity of the precursor peptide when the scaffold itself contains relevant pharmacophore elements. Therefore, quasi-peptides still maintain their appeal for applications in medicinal chemistry. For the large number of different unnatural amino acids and peptidomimetics, the overview cannot be all-inclusive. This review focuses on modified peptides in which the peptide character is still preponderant, with particular emphasis on the chemical methodologies utilized to introduce the modifications.
Topics: Animals; Cyclization; Drug Design; Humans; Molecular Structure; Peptides; Peptidomimetics
PubMed: 20687878
DOI: 10.2174/138161210793292555 -
Structure (London, England : 1993) May 2015The huge conformational space stemming from the inherent flexibility of peptides is among the main obstacles to successful and efficient computational modeling of...
The huge conformational space stemming from the inherent flexibility of peptides is among the main obstacles to successful and efficient computational modeling of protein-peptide interactions. Current peptide docking methods typically overcome this challenge using prior knowledge from the structure of the complex. Here we introduce AnchorDock, a peptide docking approach, which automatically targets the docking search to the most relevant parts of the conformational space. This is done by precomputing the free peptide's structure and by computationally identifying anchoring spots on the protein surface. Next, a free peptide conformation undergoes anchor-driven simulated annealing molecular dynamics simulations around the predicted anchoring spots. In the challenging task of a completely blind docking test, AnchorDock produced exceptionally good results (backbone root-mean-square deviation ≤ 2.2Å, rank ≤15) for 10 of 13 unbound cases tested. The impressive performance of AnchorDock supports a molecular recognition pathway that is driven via pre-existing local structural elements.
Topics: Binding Sites; Computational Biology; Databases, Protein; Models, Molecular; Molecular Docking Simulation; Peptides; Protein Binding; Protein Conformation; Software
PubMed: 25914054
DOI: 10.1016/j.str.2015.03.010 -
Journal of Chemical Theory and... Jun 2022PSD-95/discs-large/ZO-1 (PDZ) domains form a large family of adaptor proteins that bind to the C-terminal tails of their binding partner proteins. Via extensive...
PSD-95/discs-large/ZO-1 (PDZ) domains form a large family of adaptor proteins that bind to the C-terminal tails of their binding partner proteins. Via extensive molecular dynamics simulations and alchemical free energy calculations, we characterized the binding modi of phosphorylated and unphosphorylated EQVSAV peptides and of a EQVEAV phosphate mimic to the hPTP1E PDZ2 and MAGI1 PDZ1 domains. The simulations reproduced the well-known binding characteristics such as tight coordination of the peptidic carboxyl tail and pronounced hydrogen bonding between the peptide backbone and the backbone atoms of a β-sheet in PDZ. Overall, coordination by hPTP1E PDZ2 appeared tighter than by MAGI1 PDZ1. Simulations of wild-type PDZ and arginine mutants suggest that contacts with Arg79/85 in hPTP1E/MAGI1 are more important for the EQVEAV peptide than for EQVSAV. Alchemical free energy calculations and PaCS-MD simulations could well reproduce the difference in binding free energy between unphosphorylated EQVSAV and EQVEAV peptides and the absolute binding free energy of EQVSAV. However, likely due to small force field inaccuracies, the simulations erroneously favored binding of the phosphorylated peptide instead of its unphosphorylated counterpart, which is in contrast to the experiment.
Topics: Amino Acid Sequence; Carrier Proteins; Hydrogen Bonding; Molecular Dynamics Simulation; PDZ Domains; Peptides; Protein Binding
PubMed: 35608157
DOI: 10.1021/acs.jctc.1c01140 -
Methods in Molecular Biology (Clifton,... 2017Protein-protein interactions (PPIs) play a central role in almost all cellular processes. Recent technological advances have enabled the elucidation of an incredibly...
Protein-protein interactions (PPIs) play a central role in almost all cellular processes. Recent technological advances have enabled the elucidation of an incredibly complex PPI network within the cell. However, protein interactions driven by posttranslational modifications (PTMs) such as phosphorylation, which comprises a significant part of the PPI network, have proven difficult to decipher systematically. Herein, we describe a reciprocal protein-peptide array strategy to uncover PPIs mediated by tyrosine phosphorylation and the Src homology 2 (SH2) domain. This strategy, namely combining peptide and protein domain arrays for PPI mapping, may be applicable for other peptide-binding modules.
Topics: Computational Biology; Humans; Peptides; Phosphopeptides; Phosphorylation; Protein Array Analysis; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Protein Interaction Maps; Recombinant Fusion Proteins; src Homology Domains
PubMed: 28092048
DOI: 10.1007/978-1-4939-6762-9_25 -
The Journal of Pharmacology and... Jan 2013Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation...
Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation.
Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and humans. We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded. After oral administration of linaclotide, <1% of the dose was excreted as active peptide in rat feces and a mean of 3-5% in human feces; in both cases MM-419447 was the predominant peptide recovered. MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3',5'-monophosphate (cGMP). In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. These results demonstrate the importance of the active metabolite in contributing to linaclotide's pharmacology.
Topics: Alkylation; Animals; Area Under Curve; Biological Availability; Biotransformation; Constipation; Cyclic AMP; Feces; Female; Gastrointestinal Transit; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Intestinal Mucosa; Intestines; Irritable Bowel Syndrome; Male; Peptide Hydrolases; Peptides; Radioligand Assay; Rats; Rats, Sprague-Dawley
PubMed: 23090647
DOI: 10.1124/jpet.112.199430 -
Journal of the American Chemical Society Aug 2023Peptide hormones are essential signaling molecules with therapeutic importance. Identifying regulatory factors that drive their activity gives important insight into...
Peptide hormones are essential signaling molecules with therapeutic importance. Identifying regulatory factors that drive their activity gives important insight into their mode of action and clinical development. In this work, we demonstrate the combined impact of Cu(II) and the serum protein albumin on the activity of C-peptide, a 31-mer peptide derived from the same prohormone as insulin. C-peptide exhibits beneficial effects, particularly in diabetic patients, but its clinical use has been hampered by a lack of mechanistic understanding. We show that Cu(II) mediates the formation of ternary complexes between albumin and C-peptide and that the resulting species depend on the order of addition. These ternary complexes notably alter peptide activity, showing differences from the peptide or Cu(II)/peptide complexes alone in redox protection as well as in cellular internalization of the peptide. In standard clinical immunoassays for measuring C-peptide levels, the complexes inflate the quantitation of the peptide, suggesting that such adducts may affect biomarker quantitation. Altogether, our work points to the potential relevance of Cu(II)-linked C-peptide/albumin complexes in the peptide's mechanism of action and application as a biomarker.
Topics: Humans; Serum Albumin; Copper; C-Peptide; Peptides; Oxidation-Reduction
PubMed: 37486968
DOI: 10.1021/jacs.3c04599 -
Peptides 1997Rational drug design and the targeting of specific organs has become a reality in modern drug development, with the emergence of molecular biology and receptor chemistry... (Review)
Review
Rational drug design and the targeting of specific organs has become a reality in modern drug development, with the emergence of molecular biology and receptor chemistry as powerful tools for the pharmacologist. A greater understanding of peptide function as one of the major extracellular message systems has made neuropeptides an important target in neuropharmaceutical drug design. The major obstacle to targeting the brain with therapeutics is the presence of the blood-brain barrier (BBB), which controls the concentration and entry of solutes into the central nervous system. Peptides are generally polar in nature, do not easily cross the blood-brain barrier by diffusion, and except for a small number do not have specific transport systems. Peptides can also undergo metabolic deactivation by peptidases of the blood, brain and the endothelial cells that comprise the BBB. In this review, we discuss a number of the recent strategies which have been used to promote peptide stability and peptide entry into the brain. In addition, we approach the subject of targeting specific transport systems that can be found on the brain endothelial cells, and describe the limitations of the methodologies that are currently used to study brain entry of neuropharmaceuticals.
Topics: Animals; Biological Availability; Biological Transport; Blood-Brain Barrier; Brain; Humans; Peptides
PubMed: 9392847
DOI: 10.1016/s0196-9781(97)00242-8 -
Molecules (Basel, Switzerland) Oct 2017Cyclodipeptides (CDP) represent a diverse family of small, highly stable, cyclic peptides that are produced as secondary functional metabolites or side products of... (Review)
Review
Cyclodipeptides (CDP) represent a diverse family of small, highly stable, cyclic peptides that are produced as secondary functional metabolites or side products of protein metabolism by bacteria, fungi, and animals. They are widespread in nature, and exhibit a broad variety of biological and pharmacological activities. CDP synthases (CDPSs) and non-ribosomal peptide synthetases (NRPSs) catalyze the biosynthesis of the CDP core structure, which is further modified by tailoring enzymes often associated with CDP biosynthetic gene clusters. In this review, we provide a comprehensive summary of CDP biosynthetic pathways and modifying enzymes. We also discuss the biological properties of some known CDPs and their possible applications in metabolic engineering.
Topics: Biosynthetic Pathways; Dipeptides; Peptides, Cyclic
PubMed: 29065531
DOI: 10.3390/molecules22101796 -
Hormone and Metabolic Research =... 2004A role for glucagon-like peptide 1 (GLP-1) has been suggested in stimulating beta-cell lipolysis via elevation of cAMP and activation of protein kinase A, which in turn...
A role for glucagon-like peptide 1 (GLP-1) has been suggested in stimulating beta-cell lipolysis via elevation of cAMP and activation of protein kinase A, which in turn may activate hormone-sensitive lipase (HSL), thereby contributing to fatty acid generation (FFA) from intracellular triglyceride stores. FFAs may then be metabolized to a lipid signal, which is required for optimal glucose-stimulated insulin secretion. Since HSL is expressed in islet beta-cells, this effect could contribute to the stimulation of insulin secretion by GLP-1, provided that a lipid signal of importance for insulin secretion is generated. To examine this hypothesis, we have studied the acute effect of GLP-1 on isolated mouse islets from normal mice and from mice with high-fat diet induced insulin resistance. We found, however, that although GLP-1 (100 nM) markedly potentiated glucose-stimulated insulin secretion from islets of both feeding groups, the peptide was not able to stimulate islet palmitate oxidation or increase lipolysis measured as glycerol release. This indicates that a lipid signal does not contribute to the acute stimulation of insulin secretion by GLP-1. To test whether lipolysis might be involved in the islet effects of long-term GLP-1 action, mice from the two feeding groups were chronically treated with exendin-4, a peptide that lowers blood glucose by interacting with GLP-1 receptors, in order to stimulate insulin secretion, for 16 days before isolation of the islets. The insulinotropic effects of GLP-1 and forskolin were exaggerated in isolated islets from exendin-4 treated mice given a high-fat diet, with a augmented palmitate oxidation as well as islet lipolysis at high glucose levels in these islets. Exendin-4 treatment had less impact on mice fed a normal diet. From these results we conclude that while GLP-1 does not seem to induce beta-cell lipolysis acutely in mouse islets, the peptide affects beta-cell fat metabolism after long-term adaptation to GLP-1 receptor stimulation.
Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Exenatide; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Lipolysis; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptides; Protein Precursors; Venoms
PubMed: 15655711
DOI: 10.1055/s-2004-826166