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International Journal of Molecular... Dec 2020Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to... (Review)
Review
Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function.
Topics: Animals; Biomarkers; Disease Susceptibility; Glycosylation; Humans; Ligands; Oxidation-Reduction; Peptides; Protein Binding; Protein Multimerization; Protein Processing, Post-Translational; Proteolysis; Structure-Activity Relationship; alpha 1-Antitrypsin
PubMed: 33276468
DOI: 10.3390/ijms21239187 -
Molecular Pharmacology Nov 2019Many physiologic processes are controlled through the activation of G protein-coupled receptors (GPCRs) by regulatory peptides, making peptide GPCRs particularly useful... (Review)
Review
Many physiologic processes are controlled through the activation of G protein-coupled receptors (GPCRs) by regulatory peptides, making peptide GPCRs particularly useful targets for major human diseases such as diabetes and cancer. Peptide GPCRs are also being evaluated as next-generation targets for the development of novel antiparasite agents and insecticides in veterinary medicine and agriculture. Resolution of crystal structures for several peptide GPCRs has advanced our understanding of peptide-receptor interactions and fueled interest in correlating peptide heterogeneity with receptor-binding properties. In this review, the knowledge of recently crystalized peptide-GPCR complexes, previously accumulated peptide structure-activity relationship studies, receptor mutagenesis, and sequence alignment are integrated to better understand peptide binding to the transmembrane cavity of class A GPCRs. Using SAR data, we show that peptide class A GPCRs can be divided into groups with distinct hydrophilic residues. These characteristic residues help explain the preference of a receptor to bind the C-terminal free carboxyl group, the C-terminal amidated group, or the N-terminal ammonium group of peptides.
Topics: Amino Acid Sequence; Animals; Crystallography, X-Ray; Humans; Peptides; Protein Binding; Protein Structure, Secondary; Receptors, G-Protein-Coupled
PubMed: 31436539
DOI: 10.1124/mol.119.115915 -
Current Opinion in Structural Biology Feb 2024During protein synthesis, the growing nascent peptide chain moves inside the polypeptide exit tunnel of the ribosome from the peptidyl transferase center towards the... (Review)
Review
During protein synthesis, the growing nascent peptide chain moves inside the polypeptide exit tunnel of the ribosome from the peptidyl transferase center towards the exit port where it emerges into the cytoplasm. The ribosome defines the unique energy landscape of the pioneering round of protein folding. The spatial confinement and the interactions of the nascent peptide with the tunnel walls facilitate formation of secondary structures, such as α-helices. The vectorial nature of protein folding inside the tunnel favors local intra- and inter-molecular interactions, thereby inducing cotranslational folding intermediates that do not form upon protein refolding in solution. Tertiary structures start to fold in the lower part of the tunnel, where interactions with the ribosome destabilize native protein folds. The present review summarizes the recent progress in understanding the driving forces of nascent protein folding inside the tunnel and at the surface of the ribosome.
Topics: Protein Folding; Ribosomes; Protein Biosynthesis; Proteins; Peptides
PubMed: 38071940
DOI: 10.1016/j.sbi.2023.102740 -
Nature Communications Dec 2023Peptide hormones and neuropeptides are signaling molecules that control diverse aspects of mammalian homeostasis and physiology. Here we provide evidence for the...
Peptide hormones and neuropeptides are signaling molecules that control diverse aspects of mammalian homeostasis and physiology. Here we provide evidence for the endogenous presence of a sequence diverse class of blood-borne peptides that we call "capped peptides." Capped peptides are fragments of secreted proteins and defined by the presence of two post-translational modifications - N-terminal pyroglutamylation and C-terminal amidation - which function as chemical "caps" of the intervening sequence. Capped peptides share many regulatory characteristics in common with that of other signaling peptides, including dynamic physiologic regulation. One capped peptide, CAP-TAC1, is a tachykinin neuropeptide-like molecule and a nanomolar agonist of mammalian tachykinin receptors. A second capped peptide, CAP-GDF15, is a 12-mer peptide cleaved from the prepropeptide region of full-length GDF15 that, like the canonical GDF15 hormone, also reduces food intake and body weight. Capped peptides are a potentially large class of signaling molecules with potential to broadly regulate cell-cell communication in mammalian physiology.
Topics: Animals; Neuropeptides; Tachykinins; Cell Communication; Protein Processing, Post-Translational; Peptide Hormones; Mammals
PubMed: 38065934
DOI: 10.1038/s41467-023-43857-0 -
Drug Discovery Today Apr 2021Owing to their structural diversity, peptides are a unique source of innovative active ingredients. However, their development has been challenging because of their... (Review)
Review
Owing to their structural diversity, peptides are a unique source of innovative active ingredients. However, their development has been challenging because of their disadvantageous pharmacokinetic (PK) properties. Over the past decade, many attempts have been made to improve the oral bioavailability of peptide drugs. In this review, we highlight the most recent and promising techniques aimed at the improvement of the oral bioavailability of peptides. The most recent findings will influence future approaches of pharmaceutical companies in the development of new, more efficient, and safer orally delivered peptides.
Topics: Administration, Oral; Biological Availability; Drug Delivery Systems; Drug Discovery; Humans; Peptides
PubMed: 33497830
DOI: 10.1016/j.drudis.2021.01.020 -
Angewandte Chemie (International Ed. in... May 2021Proteolysis of proteins and peptides is involved in the infection of cells by enveloped viruses and also in the invasion and spread of cancer cells. Shutting down...
Proteolysis of proteins and peptides is involved in the infection of cells by enveloped viruses and also in the invasion and spread of cancer cells. Shutting down broad-specificity proteases, however, is problematic because normal functions by these proteases will be affected. Herein, nanoparticle receptors were prepared from molecular imprinting for complex biological peptides. Their strong and selective binding enabled them to protect their targeted sequences from proteolysis in aqueous solution at stoichiometric amounts. Generality of the method was demonstrated by the protection of hydrophobic and hydrophilic peptides from different proteases, selective protection of a segment of a long peptide, and selective protection of a targeted peptide in a mixture. Most interestingly, two receptors targeting different parts of a long peptide could work in cooperation to protect the overall sequence, highlighting the versatility of the method.
Topics: Peptide Hydrolases; Peptides; Proteolysis
PubMed: 33725413
DOI: 10.1002/anie.202102148 -
Chimia Jun 2021This review on intracellular delivery and oral bioavailability of peptides reflects a number of principal investigations at Novartis. Our studies were aimed at either... (Review)
Review
This review on intracellular delivery and oral bioavailability of peptides reflects a number of principal investigations at Novartis. Our studies were aimed at either understanding features enabling peptides to interfere with intracellular protein-protein interactions, or to achieve a more patient-friendly delivery by the oral route. In the light of these objectives, we have also spent some effort on assay development to come up with alternative methods for monitoring cellular peptide uptake. This summary of our insights is intended to help in the assessment and development of peptide therapeutics requiring membrane transition.
Topics: Administration, Oral; Biological Availability; Biological Transport; Humans; Peptides; Permeability
PubMed: 34233817
DOI: 10.2533/chimia.2021.522 -
Organic & Biomolecular Chemistry Jul 2022The tumor suppressor and master gene regulator protein p53 has been the subject of intense investigation for several decades due to its mutation in about half of all... (Review)
Review
The tumor suppressor and master gene regulator protein p53 has been the subject of intense investigation for several decades due to its mutation in about half of all human cancers. However, mechanistic studies of p53 in cells are complicated by its many dynamic binding partners and heterogeneous post-translational modifications. The design of therapeutics that rescue p53 functions in cells requires a mechanistic understanding of its protein-protein interactions in specific protein complexes and identifying changes in p53 activity by diverse post-translational modifications. This review highlights the important roles that peptide and protein chemistry have played in biophysical and biochemical studies aimed at elucidating p53 regulation by several key binding partners. The design of various peptide inhibitors that rescue p53 function in cells and new opportunities in targeting p53-protein interactions are discussed. In addition, the review highlights the importance of a protein semisynthesis approach to comprehend the role of site-specific PTMs in p53 regulation.
Topics: Humans; Mutation; Neoplasms; Peptides; Protein Processing, Post-Translational; Tumor Suppressor Protein p53
PubMed: 35786742
DOI: 10.1039/d2ob00902a -
PLoS Computational Biology Feb 2022In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B...
In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B cell and T cell epitope prediction has been directed exclusively towards peptidic antigens. Nevertheless, various non-peptidic molecular classes can be recognized by immune cells. These compounds have not been systematically studied yet, and prediction approaches are lacking. The ability to predict the epitope activity of non-peptidic compounds could have vast implications; for example, for immunogenic risk assessment of the vast number of drugs and other xenobiotics. Here we present the first general attempt to predict the epitope activity of non-peptidic compounds using the Immune Epitope Database (IEDB) as a source for positive samples. The molecules stored in the Chemical Entities of Biological Interest (ChEBI) database were chosen as background samples. The molecules were clustered into eight homogeneous molecular groups, and classifiers were built for each cluster with the aim of separating the epitopes from the background. Different molecular feature encoding schemes and machine learning models were compared against each other. For those models where a high performance could be achieved based on simple decision rules, the molecular features were then further investigated. Additionally, the findings were used to build a web server that allows for the immunogenic investigation of non-peptidic molecules (http://tools-staging.iedb.org/np_epitope_predictor). The prediction quality was tested with samples from independent evaluation datasets, and the implemented method received noteworthy Receiver Operating Characteristic-Area Under Curve (ROC-AUC) values, ranging from 0.69-0.96 depending on the molecule cluster.
Topics: Area Under Curve; Epitopes, B-Lymphocyte; Epitopes, T-Lymphocyte; Peptides; ROC Curve
PubMed: 35180214
DOI: 10.1371/journal.pcbi.1009151 -
Frontiers in Endocrinology 2020The Src homology 2 (SH2) domain has a special role as one of the cornerstone examples of a "modular" domain. The interactions of this domain are very well-conserved, and... (Review)
Review
The Src homology 2 (SH2) domain has a special role as one of the cornerstone examples of a "modular" domain. The interactions of this domain are very well-conserved, and have long been described as a bidentate, or "two-pronged plug" interaction between the domain and a phosphotyrosine (pTyr) peptide. Recent work has, however, highlighted unusual features of the SH2 domain that illustrate a greater diversity than was previously appreciated. In this review we discuss some of the novel and unusual characteristics across the SH2 family, including unusual peptide binding pockets, multiple pTyr recognition sites, recognition sites for unphosphorylated peptides, and recently identified variability in the conserved FLVR motif.
Topics: Animals; Binding Sites; Humans; Models, Molecular; Phosphopeptides; Phosphorylation; Phosphotyrosine; Protein Binding; src Homology Domains
PubMed: 33042028
DOI: 10.3389/fendo.2020.575220