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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 -
Endocrinology Feb 2022Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to gonadotropin-releasing hormone (GnRH) neurons for the coordinated release of... (Review)
Review
Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to gonadotropin-releasing hormone (GnRH) neurons for the coordinated release of gonadotropins, estrous cyclicity, and ovulation. But maintaining reproductive functions is metabolically demanding so there must be a coordination with multiple homeostatic functions, and it is apparent that Kiss1 neurons play that role. There are 2 distinct populations of hypothalamic Kiss1 neurons, namely arcuate nucleus (Kiss1ARH) neurons and anteroventral periventricular and periventricular nucleus (Kiss1AVPV/PeN) neurons in rodents, both of which excite GnRH neurons via kisspeptin release but are differentially regulated by ovarian steroids. Estradiol (E2) increases the expression of kisspeptin in Kiss1AVPV/PeN neurons but decreases its expression in Kiss1ARH neurons. Also, Kiss1ARH neurons coexpress glutamate and Kiss1AVPV/PeN neurons coexpress gamma aminobutyric acid (GABA), both of which are upregulated by E2 in females. Also, Kiss1ARH neurons express critical metabolic hormone receptors, and these neurons are excited by insulin and leptin during the fed state. Moreover, Kiss1ARH neurons project to and excite the anorexigenic proopiomelanocortin neurons but inhibit the orexigenic neuropeptide Y/Agouti-related peptide neurons, highlighting their role in regulating feeding behavior. Kiss1ARH and Kiss1AVPV/PeN neurons also project to the preautonomic paraventricular nucleus (satiety) neurons and the dorsomedial nucleus (energy expenditure) neurons to differentially regulate their function via glutamate and GABA release, respectively. Therefore, this review will address not only how Kiss1 neurons govern GnRH release, but how they control other homeostatic functions through their peptidergic, glutamatergic and GABAergic synaptic connections, providing further evidence that Kiss1 neurons are the key neurons coordinating energy states with reproduction.
Topics: Animals; Body Temperature Regulation; Brain Chemistry; Energy Metabolism; Female; Gonadotropin-Releasing Hormone; Homeostasis; Humans; Hypothalamus; Kisspeptins; Luteinizing Hormone; Neurons; RNA, Messenger; Reproduction
PubMed: 34953135
DOI: 10.1210/endocr/bqab253 -
Methods in Molecular Biology (Clifton,... 2020The process of creating a model of the structure formed by a pair of interacting molecules is commonly referred to as docking. Protein docking is one of the most studied...
The process of creating a model of the structure formed by a pair of interacting molecules is commonly referred to as docking. Protein docking is one of the most studied topics in computational and structural biology with applications to drug design and beyond. In this chapter, we describe ClusPro, a web server for protein-protein and protein-peptide docking. As an input, the server requires two Protein Data Bank (PDB) files (protein-protein mode) or a PDB file for the protein and a sequence for the ligand (protein-peptide mode). Its output consists of ten models of the resulting structure formed by the two objects upon interaction. The server typically produces results in less than 4 h. The server also provides tools (via "Advanced Options" list) for a user to fine-tune the results using any additional knowledge about the interaction process, e.g., small-angle X-ray scattering (SAXS) profile or distance restraints.
Topics: Binding Sites; Molecular Docking Simulation; Peptides; Protein Binding; Protein Conformation; Sequence Analysis, Protein; Software
PubMed: 32621224
DOI: 10.1007/978-1-0716-0708-4_9 -
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 -
The Journal of Biological Chemistry Oct 2023Family B2 or adhesion G protein-coupled receptors (AGPCRs) are distinguished by variable extracellular regions that contain a modular protease, termed the GPCR...
Family B2 or adhesion G protein-coupled receptors (AGPCRs) are distinguished by variable extracellular regions that contain a modular protease, termed the GPCR autoproteolysis-inducing domain that self-cleaves the receptor into an N-terminal fragment (NTF) and a C-terminal fragment (CTF), or seven transmembrane domain (7TM). The NTF and CTF remain bound after cleavage through noncovalent interactions. NTF binding to a ligand(s) presented by nearby cells, or the extracellular matrix anchors the NTF, such that cell movement generates force to induce NTF/CTF dissociation and expose the AGPCR tethered peptide agonist. The released tethered agonist (TA) binds rapidly to the 7TM orthosteric site to activate signaling. The orphan AGPCR, GPR114 was reported to be uncleaved, yet paradoxically capable of activation by its TA. GPR114 has an identical cleavage site and TA to efficiently cleave GPR56. Here, we used immunoblotting and biochemical assays to demonstrate that GPR114 is a cleaved receptor, and the self-cleavage is required for GPR114 TA-activation of Gs and no other classes of G proteins. Mutagenesis studies defined features of the GPR114 and GPR56 GAIN subdomains that influenced self-cleavage efficiency. Thrombin treatment of protease-activated receptor 1 leader/AGPCR fusion proteins demonstrated that acute decryption of the GPR114/56 TAs activated signaling. GPR114 was found to be expressed in an eosinophilic-like cancer cell line (EoL-1 cells) and endogenous GPR114 was efficiently self-cleaved. Application of GPR114 TA peptidomimetics to EoL-1 cells stimulated cAMP production. Our findings may aid future delineation of GPR114 function in eosinophil cAMP signaling related to migration, chemotaxis, or degranulation.
Topics: Cell Adhesion; Peptides; Protein Binding; Protein Domains; Receptors, G-Protein-Coupled; Signal Transduction; Humans
PubMed: 37673336
DOI: 10.1016/j.jbc.2023.105223 -
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 -
Nature Reviews. Drug Discovery Jun 2020Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides... (Review)
Review
Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) - nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first-in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties.
Topics: Animals; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Humans; Ligands; Molecular Targeted Therapy; Peptide Library; Peptides; Protein Binding; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 32494050
DOI: 10.1038/s41573-020-0062-z -
Journal of the American Chemical Society Mar 2022Peptides are fundamental therapeutic modalities whose sequence-specific synthesis can be automated. Yet, modern peptide synthesis remains atom uneconomical and requires...
Peptides are fundamental therapeutic modalities whose sequence-specific synthesis can be automated. Yet, modern peptide synthesis remains atom uneconomical and requires an excess of coupling agents and protected amino acids for efficient amide bond formation. We recently described the rational design of an organocatalyst that can operate on Fmoc amino acids─the standard monomers in automated peptide synthesis ( , 141, 15977). The catalytic cycle centered on the conversion of the carboxylic acid to selenoester, which was activated by a hydrogen bonding scaffold for amine coupling. The selenoester was generated from a diselenide catalyst and stoichiometric amounts of phosphine. Although the prior system catalyzed oligopeptide synthesis on solid phase, it had two significant requirements that limited its utility as an alternative to coupling agents─it depended on stoichiometric amounts of phosphine and required molecular sieves as dehydrating agent. Here, we address these limitations with an optimized method that requires only catalytic amounts of phosphine and no dehydrating agent. The new method utilizes a two-component organoreductant/organooxidant-recycling strategy to catalyze amide bond formation.
Topics: Amides; Amines; Amino Acids; Oxidation-Reduction; Peptide Biosynthesis; Peptides
PubMed: 35188383
DOI: 10.1021/jacs.1c12798 -
Biomolecules Jan 2022The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area... (Review)
Review
The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, "hot spots", as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ-TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.
Topics: Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Peptides; Protein Binding
PubMed: 35053254
DOI: 10.3390/biom12010106