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Methods in Molecular Biology (Clifton,... 2017In this chapter we present two methods related to rational design of inhibitory peptides: PepCrawler: A tool to derive binding peptides from protein-protein complexes...
In this chapter we present two methods related to rational design of inhibitory peptides: PepCrawler: A tool to derive binding peptides from protein-protein complexes and the prediction of protein-peptide complexes. Given an initial protein-peptide complex, the method detects improved predicted peptide binding conformations which bind the protein with higher affinity. This program is a robotics motivated algorithm, representing the peptide as a robotic arm moving among obstacles and exploring its conformational space in an efficient way. PinaColada: A peptide design program for the discovery of novel peptide candidates that inhibit protein-protein interactions. PinaColada uses PepCrawler while introducing sequence mutations, in order to find novel inhibitory peptides for PPIs. It uses the ant colony optimization approach to explore the peptide's sequence space, while using PepCrawler in the refinement stage.
Topics: Algorithms; Computational Biology; Drug Design; Humans; Models, Molecular; Peptide Fragments; Protein Binding; Protein Conformation; Protein Interaction Maps; Proteins
PubMed: 28236244
DOI: 10.1007/978-1-4939-6798-8_16 -
ACS Chemical Biology Aug 2022The methylation of peptide backbone amides is a hallmark of bioactive natural products, and it also greatly modifies the pharmacology of synthetic peptides. Usually,...
The methylation of peptide backbone amides is a hallmark of bioactive natural products, and it also greatly modifies the pharmacology of synthetic peptides. Usually, bioactive -methylated peptides are cyclic. However, there is very limited knowledge about how post-translational enzymes can be applied to the synthesis of designed -methylated peptides or peptide libraries. Here, driven by the established ability of some RiPP enzymes to process diverse substrates, we sought to define catalysts for the and macrocyclization of backbone-methylated peptides. We developed efficient methods in which short, synthetic -methylated peptides could be modified using side chain and mainchain macrocyclases, PsnB and PCY1 from plesiocin and orbitide biosynthetic pathways, respectively. Most significantly, a strategy for PsnB cyclase was designed enabling simple in vitro methods compatible with solid-phase peptide synthesis. We show that cyanobactin N-terminal protease PatA is a broadly useful catalyst that is also compatible with -methylation chemistry, but that cyanobactin macrocyclase PatG is strongly biased against -methylated substrates. Finally, we sought to marry these macrocyclase tools with an enzyme that -methylates its core peptide: OphMA from the omphalotin pathway. However, instead, we reveal some limitations of OphMA and demonstrate that it unexpectedly and extensively modified the enzyme itself . Together, these results demonstrate proof-of-concept for enzymatic synthesis of -methylated peptide macrocycles.
Topics: Biosynthetic Pathways; Methylation; Peptide Hydrolases; Peptides; Peptides, Cyclic; Protein Processing, Post-Translational
PubMed: 35819062
DOI: 10.1021/acschembio.2c00293 -
Biochemistry Jan 2023Kinases are responsible for regulating cellular and physiological processes, and abnormal kinase activity is associated with various diseases. Therefore, kinases are...
Kinases are responsible for regulating cellular and physiological processes, and abnormal kinase activity is associated with various diseases. Therefore, kinases are being used as biomarkers for disease and developing methods for their sensing is highly important. Usually more than one kinase is involved in phosphorylating a target protein. However, kinase detection methods usually detect the activity of only one specific kinase. Here we describe an electrochemical kinase sensing tool for the selective detection of two kinases using the same target peptide. We demonstrate the sensing of kinases ERK2 and PKCδ. This is based on a single sensing element, a peptide that contains two distinct phosphorylation sites of these two kinases. Reversibility experiments with alkaline phosphatase and reaction with the electrochemically active ferrocene-labeled ATP showed that the mechanism of sensing is by detecting the enzymatic phosphorylation. Our approach can be further utilized to develop devices for the detection of multiple kinases and can be expanded to other types of enzymes involved in disease.
Topics: Phosphorylation; Peptides; MAP Kinase Signaling System
PubMed: 36239671
DOI: 10.1021/acs.biochem.2c00411 -
Accounts of Chemical Research Oct 2008For more than a decade now, a search for answers to the following two questions has taken us on a new and exciting journey into the world of beta- and gamma-peptides:...
For more than a decade now, a search for answers to the following two questions has taken us on a new and exciting journey into the world of beta- and gamma-peptides: What happens if the oxygen atoms in a 3i-helix of a polymeric chain composed of (R)-3-hydroxybutanoic acid are replaced by NH units? What happens if one or two CH2 groups are introduced into each amino acid building block in the chain of a peptide or protein, thereby providing homologues of the proteinogenic alpha-amino acids? Our journey has repeatedly thrown up surprises, continually expanding the potential of these classes of compound and deepening our understanding of the structures, properties, and multifaceted functions of the natural "models" to which they are related. Beta-peptides differ from their natural counterparts, the alpha-peptides, by having CH2 groups inserted into every amino acid residue, either between the C=O groups and the alpha-carbon atoms (beta(3)) or between the alpha-carbon and nitrogen atoms (beta(2)). The synthesis of these homologated proteinogenic amino acids and their assembly into beta-peptides can be performed using known methods. Despite the increased number of possible conformers, the beta-peptides form secondary structures (helices, turns, sheets) even when the chain lengths are as short as four residues. Furthermore, they are stable toward degrading and metabolizing enzymes in living organisms. Linear, helical, and hairpin-type structures of beta-peptides can now be designed in such a way that they resemble the characteristic and activity-related structural features ("epitopes") of corresponding natural peptides or protein sections. This Account presents examples of beta-peptidic compounds binding, as agonists or antagonists (inhibitors), to (i) major histocompatibility complex (MHC) proteins (immune response), (ii) the lipid-transport protein SR-B1 (cholesterol uptake from the small intestine), (iii) the core (1-60) of interleukin-8 (inflammation), (iv) the oncoprotein RDM2, (v) the HIVgp41 fusion protein, (vi) G-protein-coupled somatostatin hsst receptors, (vii) the TNF immune response receptor CD40 (apoptosis), and (viii) DNA. Short-chain beta-peptides may be orally bioavailable and excreted from the body of mammals; long-chain beta-peptides may require intravenous administration but will have longer half-lives of clearance. It has been said that an interesting field of research distinguishes itself in that the results always throw up new questions; in this sense, the structural and biological investigation of beta-peptides has been a gold mine. We expect that these peptidic peptidomimetics will play an increasing role in biomedical research and drug development in the near future.
Topics: Amino Acids; Animals; Biomimetic Materials; DNA; Killer Cells, Natural; Models, Molecular; Molecular Structure; Peptides; Protein Binding; Proteins; RNA; Rats
PubMed: 18578513
DOI: 10.1021/ar700263g -
Current Opinion in Chemical Biology Aug 2023Inhibitors for epigenetic readers of histone modifications are useful chemical probes to interrogate the functional roles played by their cognate targets in epigenetic... (Review)
Review
Inhibitors for epigenetic readers of histone modifications are useful chemical probes to interrogate the functional roles played by their cognate targets in epigenetic regulation and can even serve as drugs for the treatment of diseases associated with the dysregulated targets. However, many epigenetic readers are intractable to small molecules, as the recognition of modified histone peptides commonly involves flat and extended protein surfaces. In contrast, the relatively large sizes and structural complexity of peptides help them achieve tight and specific binding to the target proteins. Increasing efforts have been made to target epigenetic readers using peptide-based inhibitors that can complement small molecules. In this review, we discuss the recent advances in the development of peptide-based inhibitors of lysine acetylation and methylation readers.
Topics: Methylation; Histones; Epigenesis, Genetic; Lysine; Acetylation; Peptides
PubMed: 37263048
DOI: 10.1016/j.cbpa.2023.102334 -
Chemistry, An Asian Journal Jan 2018An electrochromic system based on a self-assembled dipeptide-appended redox-active quinquethiophene π-gel is reported. The designed peptide-quinquethiophene consists of...
An electrochromic system based on a self-assembled dipeptide-appended redox-active quinquethiophene π-gel is reported. The designed peptide-quinquethiophene consists of a symmetric bolaamphiphile that has two segments: a redox-active π-conjugated quinquethiophene core for electrochromism, and peptide motif for the involvement of molecular self-assembly. Investigations reveal that self-assembly and electrochromic properties of the π-gel are strongly dependent on the relative orientation of peptidic and quinquethiophene scaffolds in the self-assembly system. The colors of the π-gel film are very stable with fast and controlled switching speed at room temperature.
Topics: Electrochemical Techniques; Gels; Molecular Structure; Oxidation-Reduction; Peptides; Thiophenes
PubMed: 29266836
DOI: 10.1002/asia.201701460 -
Bioconjugate Chemistry Nov 2022Synthetic calcium transporters are few despite their potential biological significance. Herein, we report small alanine-derived peptides containing pyridyl-triazole...
Synthetic calcium transporters are few despite their potential biological significance. Herein, we report small alanine-derived peptides containing pyridyl-triazole motifs for inducing calcium selectivity. The peptides are decorated with hydrophobic alkyl chains to facilitate membrane insertion. The most efficient peptide scaffold has an EC value of 0.09 mol % and functions as a calcium carrier.
Topics: Ionophores; Calcium; Peptides; Biological Transport; Ion Transport
PubMed: 36345049
DOI: 10.1021/acs.bioconjchem.2c00396 -
Current Medicinal Chemistry May 2002The discovery of peptide hormones, growth factors and neuropeptides implicated in vital biological functions of our organism has increased interest in therapeutic use of... (Review)
Review
The discovery of peptide hormones, growth factors and neuropeptides implicated in vital biological functions of our organism has increased interest in therapeutic use of short peptides. However, the development of peptides as clinically useful drugs is greatly limited by their poor metabolic stability and low bioavailability, which is due in part to their inability to readily cross membrane barriers such as the intestinal and blood-brain barriers. The aim of peptide medicinal chemistry is, therefore, to develop strategies to overcome these problems. Recent progress in chemical synthesis and design have resulted in several strategies for producing modified peptides and mimetics with lower susceptibility to proteolysis and improved bioavailability, which has increased the probability of obtaining useful drugs structurally related to parent peptides. This review describes different experimental approaches to transforming a peptide into a potential drug and provides examples of the usefulness of these strategies.
Topics: Biological Availability; Drug Stability; Peptides
PubMed: 11966456
DOI: 10.2174/0929867024606731 -
Mini Reviews in Medicinal Chemistry Jul 2010The development of an adequate immune response against pathogens is mediated by molecular interactions between different cell types. Among them, binding of antigenic... (Review)
Review
The development of an adequate immune response against pathogens is mediated by molecular interactions between different cell types. Among them, binding of antigenic peptides to the Major Histocompatibility Complex (MHC) molecule expressed on the membrane of antigen presenting cells (APCs), and their subsequent recognition by the T cell receptor have been demonstrated to be crucial for developing an adequate immune response. The present review compiles computational quantum chemistry studies about the electrostatic potential variations induced on the MHC binding region by peptide's amino acids, carried out with the aim of describing MHC-peptide binding interactions. The global idea is that the electrostatic potential can be represented in terms of a series expansion (charge, dipole, quadrupole, hexadecapole, etc.) whose three first terms provide a good local approximation to the molecular electrostatic 'landscape' and to the variations induced on such landscape by targeted modifications on the residues of the antigenic peptide. Studies carried out in four MHC class II human allele molecules, which are the most representative alleles of their corresponding haplotypes, showed that each of these molecules have conserved as well as specific electrostatic characteristics, which can be correlated at a good extent with the peptide binding profiles reported experimentally for these molecules. The information provided by such characteristics would help increase our knowledge about antigen binding and presentation, and could ultimately contribute to developing a logical and rational methodology for designing chemically synthesized, multi-antigenic, subunit-based vaccines, through the application of quantum chemistry methods.
Topics: HLA Antigens; Histocompatibility Antigens; Humans; Peptides; Protein Binding; Quantum Theory; Static Electricity; Vaccines
PubMed: 20394575
DOI: 10.2174/138955710791572488 -
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