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Organic & Biomolecular Chemistry Jan 2021DNAzymes were previously identified by in vitro selection for a variety of chemical reactions, including several biologically relevant peptide modifications. However,...
DNAzymes were previously identified by in vitro selection for a variety of chemical reactions, including several biologically relevant peptide modifications. However, finding DNAzymes for peptide lysine acylation is a substantial challenge. By using suitably reactive aryl ester acyl donors as the electrophiles, here we used in vitro selection to identify DNAzymes that acylate amines, including lysine side chains of DNA-anchored peptides. Some of the DNAzymes can transfer a small glutaryl group to an amino group. These results expand the scope of DNAzyme catalysis and suggest the future broader applicability of DNAzymes for sequence-selective lysine acylation of peptide and protein substrates.
Topics: Acylation; Amines; Biocatalysis; DNA, Catalytic; Lysine; Peptides
PubMed: 33150349
DOI: 10.1039/d0ob02015j -
Drug Development Research Nov 2021Advancement in biotechnology provided a notable expansion of peptide and protein therapeutics, used as antigens, vaccines, hormones. It has a prodigious potential to... (Review)
Review
Advancement in biotechnology provided a notable expansion of peptide and protein therapeutics, used as antigens, vaccines, hormones. It has a prodigious potential to treat a broad spectrum of diseases such as cancer, metabolic disorders, bone disorders, and so forth. Protein and peptide therapeutics are administered parenterally due to their poor bioavailability and stability, restricting their use. Hence, research focuses on the oral delivery of peptides and proteins for the ease of self-administration. In the present review, we first address the main obstacles in the oral delivery system in addition to approaches used to enhance the stability and bioavailability of peptide/protein. We describe the physiochemical parameters of the peptides and proteins influencing bioavailability in the systemic circulation. It encounters, many barriers affecting its stability, such as poor cellular membrane permeability at the GIT site, enzymatic degradation (various proteases), and first-pass hepatic metabolism. Then describe the current approaches to overcome the challenges mentioned above by the use of absorption enhancers or carriers, structural modification, formulation and advance technology.
Topics: Administration, Oral; Biological Availability; Drug Delivery Systems; Peptides; Proteins
PubMed: 33988872
DOI: 10.1002/ddr.21832 -
Journal of Chemical Information and... Feb 2022Peptide-protein interactions play a key role for many cellular and metabolic processes involved in the onset of largely spread diseases such as cancer and...
Peptide-protein interactions play a key role for many cellular and metabolic processes involved in the onset of largely spread diseases such as cancer and neurodegenerative pathologies. Despite the progress in the structural characterization of peptide-protein interfaces, the in-depth knowledge of the molecular details behind their interactions is still a daunting task. Here, we present the first comprehensive morphological and energetic study of peptide binding sites by focusing on both peptide and protein standpoints. Starting from the PixelDB database, a nonredundant benchmark collection of high-quality 3D crystallographic structures of peptide-protein complexes, a classification analysis of the most representative categories based on the nature of each cocrystallized peptide has been carried out. Several interpretable geometrical and energetic descriptors have been computed both from peptide and target protein sides in the attempt to unveil physicochemical and structural causative correlations. Finally, we investigated the most frequent peptide-protein residue pairs at the binding interface and made extensive energetic analyses, based on GRID MIFs, with the aim to study the peptide affinity-enhancing interactions to be further exploited in rational drug design strategies.
Topics: Binding Sites; Peptides; Protein Binding; Proteins
PubMed: 35148095
DOI: 10.1021/acs.jcim.1c01343 -
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 -
Current Opinion in Structural Biology Aug 2018This review details recent developments in the design of supramolecular materials with customizable properties that can be coordinated in space and time. We highlight... (Review)
Review
This review details recent developments in the design of supramolecular materials with customizable properties that can be coordinated in space and time. We highlight examples where both kinetic and thermodynamic considerations are incorporated in design, to address three challenges: control of order/disorder in supramolecular assembly; formation of structures with distinct functional domains; formation of out-of-equilibrium structures with controlled lifetimes. The examples that are discussed are based on self-assembling peptide and saccharide-based amphiphiles. These biomolecular amphiphiles are of low complexity and ideally suited to fundamental, systematic studies while they are also considered for applications in environmental remediation, food science, cosmetics and nanomedicine.
Topics: Bioengineering; Kinetics; Macromolecular Substances; Metabolic Networks and Pathways; Peptides; Structure-Activity Relationship; Sugars; Thermodynamics
PubMed: 29494797
DOI: 10.1016/j.sbi.2018.02.001 -
Methods in Enzymology 2021The chemical modification of peptides is a promising approach for the design of protein-protein interaction inhibitors and peptide-based drug candidates. Among several...
The chemical modification of peptides is a promising approach for the design of protein-protein interaction inhibitors and peptide-based drug candidates. Among several peptidomimetic strategies, substitution of the amide backbone maintains side-chain functionality that may be important for engagement of biological targets. Backbone amide substitution has been largely limited to N-alkylation, which can promote cis amide geometry and disrupt important H-bonding interactions. In contrast, N-amination of peptides induces distinct backbone geometries and maintains H-bond donor capacity. In this chapter we discuss the conformational characteristics of designed N-amino peptides and present a detailed protocol for their synthesis on solid support. The described methods allow for backbone N-amino scanning of biologically active parent sequences.
Topics: Alkylation; Amides; Molecular Conformation; Peptides; Peptidomimetics
PubMed: 34325790
DOI: 10.1016/bs.mie.2021.04.013 -
Food Chemistry Dec 2023Minerals including calcium, iron, zinc, magnesium, and copper have several human nutritional functions due to their metabolic activities. Body tissues require sufficient... (Review)
Review
Minerals including calcium, iron, zinc, magnesium, and copper have several human nutritional functions due to their metabolic activities. Body tissues require sufficient levels of a variety of micronutrients to maintain their health. To achieve these micronutrient needs, dietary consumption must be adequate. Dietary proteins may regulate the biological functions of the body in addition to acting as nutrients. Some peptides encoded in the native protein sequences are primarily responsible for the absorption and bioavailability of minerals in physiological functions. Metal-binding peptides (MBPs) were discovered as potential agents for mineral supplements. Nevertheless, sufficient studies on how MBPs affect the biological functions of minerals are lacking. The hypothesis is that the absorption and bioavailability of minerals are significantly influenced by peptides, and these properties are further enhanced by the configuration and attribute of the metal-peptide complex. In this review, the production of MBPs is discussed using various key parameters such as the protein sources and amino acid residues, enzymatic hydrolysis, purification, sequencing and synthesis and in silico analysis of MBPs. The mechanisms of metal-peptide complexes as functional food ingredients are elucidated, including metal-peptide ratio, precursors and ligands, complexation reaction, absorbability and bioavailability. Finally, the characteristics and application of different metal-peptide complexes are also described.
Topics: Humans; Biological Availability; Minerals; Iron; Diet; Peptides; Micronutrients; Chelating Agents
PubMed: 37418874
DOI: 10.1016/j.foodchem.2023.136678 -
Advances in Protein Chemistry and... 2019Nucleobindins (NUCBs) are DNA and calcium binding, secreted proteins with various signaling functions. Two NUCBs, nucleobindin-1 (NUCB1) and nucleobindin-2 (NUCB2), were... (Review)
Review
Nucleobindins (NUCBs) are DNA and calcium binding, secreted proteins with various signaling functions. Two NUCBs, nucleobindin-1 (NUCB1) and nucleobindin-2 (NUCB2), were discovered during the 1990s. These two peptides are shown to have diverse functions, including the regulation of inflammation and bone formation, among others. In 2006, Oh-I and colleagues discovered that three peptides encoded within the NUCB2 could be processed by prohormone convertases. These peptides were named nesfatin-1, 2 and 3, mainly due to the satiety and fat influencing properties of nesfatin-1. However, it was found that nesfatin-2 and -3 have no such effects. Nesfatin-1, especially its mid-segment, is very highly conserved across vertebrates. Although the receptor(s) that mediate nesfatin-1 effects are currently unknown, it is now considered an endogenous peptide with multiple functions, affecting central and peripheral tissues to regulate metabolism, reproduction, endocrine and other functions. We recently identified a nesfatin-1-like peptide (NLP) encoded within the NUCB1. Like nesfatin-1, NLP suppressed feed intake in mice and fish, and stimulated insulin secretion from pancreatic beta cells. There is considerable evidence available to indicate that nucleobindins and its encoded peptides are multifunctional regulators of cell biology and whole animal physiology. This review aims to briefly discuss the structure, distribution, functions and mechanism of action nucleobindins and encoded peptides.
Topics: Animals; Calcium; DNA; Humans; Models, Molecular; Nucleobindins; Peptides; Protein Interaction Maps; Protein Processing, Post-Translational; Signal Transduction
PubMed: 31036300
DOI: 10.1016/bs.apcsb.2019.02.001 -
Peptides Feb 2018Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational... (Review)
Review
Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Proteolysis
PubMed: 29412814
DOI: 10.1016/j.peptides.2017.10.011 -
Journal of Controlled Release :... Oct 2018Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last... (Review)
Review
Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last several decades. However, systemic delivery of therapeutic peptides via the oral route has been a daunting task due to the low pH denaturation of the peptides in the stomach, enzymatic instability, and poor transport across the tight junctions resulting in very low bioavailability. The low bioavailability is accompanied by large intra- and inter-subject variability leading to translational issues, preventing the development of successful peptide therapeutics. The inter-subject variability leads to large differences in pharmacologic responses in individuals and thus the dose required to produce therapeutic effect could vary between individuals making the development of drug product a very difficult task. A substantial amount of research has been (and continues to be) performed with a focus on getting acceptable absorption and reproducible results. Nonetheless, the high variability and low bioavailability during oral administration of peptides is still a work in progress and under-explored in a systematic way. While there are several review articles and scattered publications that discuss potential technologies for oral peptide delivery, a detailed look into the physiological challenges and absorption barriers which are a hindrance to successful clinical translation, is lacking. Herein, we have analyzed the physiological barriers within the gastrointestinal (GI) tract that are the root causes for the low bioavailability and high variability of oral delivery of peptides in humans. In particular, we have taken a detailed look at the key influencing factors such as the nature of various GI tract parameters, components of the GI tract that influences the uptake, site of absorption, pH of the gastric and intestinal compartments, food effect, and role of peptidases in affecting oral peptide absorption. Lack of in vitro - in vivo correlations and variability in animal models have also been highlighted as key impediments in understanding the challenges. The unique perspective presented herein for overcoming the physiological absorption barriers, will offer better developability approaches and will positively impact clinical translation of future oral peptide therapeutics. A deep understanding of these effects are vital, given the emergence of microbiome and oral biologic drug delivery that are fast emerging as the next wave of personalized patient centric therapies.
Topics: Administration, Oral; Animals; Biological Availability; Drug Delivery Systems; Gastrointestinal Tract; Humans; Intestinal Absorption; Peptides
PubMed: 30145135
DOI: 10.1016/j.jconrel.2018.08.032