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Srpski Arhiv Za Celokupno Lekarstvo 2014Research on the renin-angiotensin system (RAS) has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of... (Review)
Review
Research on the renin-angiotensin system (RAS) has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE) metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS) and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.
Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Guinea Pigs; Humans; Kallikrein-Kinin System; Peptidyl-Dipeptidase A; Renin-Angiotensin System
PubMed: 25731011
DOI: 10.2298/sarh1412756i -
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 -
Proteins Nov 2022Designing peptides for protein-protein interaction inhibition is of significant interest in computer-aided drug design. Such inhibitory peptides could mimic and compete...
Designing peptides for protein-protein interaction inhibition is of significant interest in computer-aided drug design. Such inhibitory peptides could mimic and compete with the binding of the partner protein to the inhibition target. Experimental peptide design is a laborious, time consuming, and expensive multi-step process. Therefore, in silico peptide design can be beneficial for achieving this task. We present a novel algorithm, Pep-Whisperer, which aims to design inhibitory peptides for protein-protein interaction. The desirable peptides would have a relatively high predicted binding affinity to the target protein in a given protein-protein complex. The algorithm outputs linear peptides which are based on an initial template. The template could either be a peptide which is retrieved from the interaction site, or a patch of nonconsecutive amino acids from the protein-protein interface which is completed to a linear peptide by short polyalanine linkers. In addition, the algorithm takes into consideration the conservation of the amino acids in the ligand-protein binding site by using evolutionary information for choosing the preferred amino acids in each position of the designed peptide. Our algorithm was able to design peptides with high predicted binding affinity to the target protein. The method is fully automated and available as a web server at http://bioinfo3d.cs.tau.ac.il/PepWhisperer/.
Topics: Amino Acids; Drug Design; Ligands; Peptides; Protein Binding; Proteins
PubMed: 35598299
DOI: 10.1002/prot.26384 -
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 -
Methods in Molecular Biology (Clifton,... 2019This review describes a selection of macrocyclic natural products and structurally modified analogs containing peptidic and non-peptidic elements as structural features... (Review)
Review
This review describes a selection of macrocyclic natural products and structurally modified analogs containing peptidic and non-peptidic elements as structural features that potentially modulate cellular permeability. Examples range from exclusively peptidic structures like cyclosporin A or phepropeptins to compounds with mostly non-peptidic character, such as telomestatin or largazole. Furthermore, semisynthetic approaches and synthesis platforms to generate general and focused libraries of compounds at the interface of cyclic peptides and non-peptidic macrocycles are discussed.
Topics: Biological Products; Cyclization; Depsipeptides; Humans; Lactones; Macrocyclic Compounds; Oxazoles; Peptide Library; Peptides, Cyclic; Permeability; Protein Conformation; Spiro Compounds; Streptogramins; Thiazoles
PubMed: 31134572
DOI: 10.1007/978-1-4939-9504-2_9 -
Analytical Chemistry Jul 2023Oxidation and protein phosphorylation are critical mechanisms involved in regulating various cellular activities. Increasing research has suggested that oxidative stress...
Oxidation and protein phosphorylation are critical mechanisms involved in regulating various cellular activities. Increasing research has suggested that oxidative stress could affect the activities of specific kinases or phosphatases, leading to alterations in the phosphorylation status of certain proteins. Ultimately, these alterations can affect cellular signaling pathways and gene expression patterns. However, the relationship between oxidation and protein phosphorylation remains complex and not yet fully understood. Therefore, the development of effective sensors capable of detecting both oxidation and protein phosphorylation simultaneously presents an ongoing challenge. To address this need, we introduce a proof-of-concept nanochannel device that is dual-responsive to both HO and phosphorylated peptide (PP). Specifically, we design a peptide GGGCEG(GPGGA)CEGRRRR, which contains an HO-sensitive unit CEG, an elastic peptide fragment (GPGGA), and a phosphorylation site recognition fragment RRRR. When the peptides are immobilized on the inner walls of conical nanochannels in a polyethylene terephthalate membrane, this peptide-modified nanochannel device exhibits a sensitive response to both HO and PPs. The peptide chains undergo a random coil-to-α-helix transition in response to HO, which leads to a close-to-open transition of the nanochannel, accompanied with a remarkable increase in the transmembrane ionic current. In contrast, binding of the peptides with PPs shields the positive charge of the RRRR fragments, causing a decrease of the transmembrane ionic current. These unique features enable the sensitive detection of reactive oxygen species released by 3T3-L1 cells stimulated by platelet-derived growth factor (PDGF) as well as PDGF-induced change in the PP level. Real-time kinase activity monitoring further confirms the device's potential utility for kinase inhibitor screening.
Topics: Hydrogen Peroxide; Peptides; Platelet-Derived Growth Factor; Phosphorylation; Oxidative Stress
PubMed: 37358224
DOI: 10.1021/acs.analchem.3c01458 -
Biotechnology Advances 2021Innovative biotechnological methods empower the successful identification of new drug candidates. Phage, ribosome and mRNA display represent high throughput screenings,... (Review)
Review
Innovative biotechnological methods empower the successful identification of new drug candidates. Phage, ribosome and mRNA display represent high throughput screenings, allowing fast and efficient progress in the field of targeted drug discovery. The identification range comprises low molecular weight peptides up to whole antibodies. However, a major challenge poses the stability and affinity in particular of peptides. Chemical modifications e.g. the introduction of unnatural amino acids or cyclization, have been proven to be essential tools to overcome these limitations. This review article particularly focuses on available methods for the targeted chemical modification of peptides and peptide libraries in selected display approaches.
Topics: Drug Discovery; High-Throughput Screening Assays; Peptide Library; Peptides; Protein Processing, Post-Translational
PubMed: 33513435
DOI: 10.1016/j.biotechadv.2021.107699 -
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 -
World Journal of Microbiology &... Jun 2017Initially discovered in the mid-twentieth century, thiopeptides constitute a diverse family of bacterially produced natural products exhibiting a remarkable array of... (Review)
Review
Initially discovered in the mid-twentieth century, thiopeptides constitute a diverse family of bacterially produced natural products exhibiting a remarkable array of biological properties. Only in the last several years have the details of thiopeptide biosynthesis been uncovered by a combination of genomic, genetic, and biochemical approaches. Thiopeptides are now known to be ribosomally synthesized and subsequently densely modified to carry azol(in)es, dehydro amino acids, and various other pathway-specific decorations. The defining feature of thiopeptides is a central six-membered nitrogenous ring that constrains peptide macrocycles of varying sequences and sizes. Recent landmark studies have defined the precisely orchestrated posttranslational modification cascade culminating in thiopeptide product formation. Because diverse thiopeptides are processed by a relatively small number of well-conserved enzymes, it has been suggested that artificial diversification of the precursor peptide could allow a vast new chemical space to be explored for clinically important activities. The success of this strategy depends on the plasticity of thiopeptide processing machinery, an open question that warrants further investigation. There is an urgent need therefore to leverage established thiopeptide research platforms to investigate substrate-enzyme specificity and devise intelligent diversification strategies for library generation. Meanwhile, the distinct genomic signatures of conserved thiopeptide-associated genes will enable the continued mining of nature for novel compounds and processing enzymes.
Topics: Amino Acids; Bacterial Proteins; Bacteriocins; Genes, Bacterial; Genomics; Molecular Structure; Multigene Family; Peptide Biosynthesis; Peptides; Protein Engineering; Protein Processing, Post-Translational; Ribosomes
PubMed: 28497389
DOI: 10.1007/s11274-017-2283-9 -
Annual Review of Pharmacology and... Jan 2017Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has... (Review)
Review
Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has been increased interest in targeting them using peptide-based therapeutics. Peptides benefit from being specific, relatively safe, and easy to produce. They are also easy to modify using chemical synthesis and molecular biology techniques. However, significant challenges remain regarding the use of peptides as therapeutic agents. Identification of peptide motifs is difficult, and peptides typically display low cell permeability and sensitivity to enzymatic degradation. In this review, we outline the principal high-throughput methodologies for motif discovery and describe current methods for overcoming pharmacokinetic and bioavailability limitations.
Topics: Animals; Drug Discovery; Humans; Peptide Library; Peptides; Protein Binding; Protein Interaction Domains and Motifs
PubMed: 27618737
DOI: 10.1146/annurev-pharmtox-010716-104805