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Nature Communications Jan 2021Azoles are five-membered heterocycles often found in the backbones of peptidic natural products and synthetic peptidomimetics. Here, we report a method of ribosomal...
Azoles are five-membered heterocycles often found in the backbones of peptidic natural products and synthetic peptidomimetics. Here, we report a method of ribosomal synthesis of azole-containing peptides involving specific ribosomal incorporation of a bromovinylglycine derivative into the nascent peptide chain and its chemoselective conversion to a unique azole structure. The chemoselective conversion was achieved by posttranslational dehydrobromination of the bromovinyl group and isomerization in aqueous media under fairly mild conditions. This method enables us to install exotic azole groups, oxazole and thiazole, at designated positions in the peptide chain with both linear and macrocyclic scaffolds and thereby expand the repertoire of building blocks in the mRNA-templated synthesis of designer peptides.
Topics: Azoles; Biomimetics; Drug Design; Peptide Biosynthesis; Peptides; Peptidomimetics; Protein Processing, Post-Translational
PubMed: 33514734
DOI: 10.1038/s41467-021-20992-0 -
International Journal of Molecular... Apr 2021Technological developments in the field of biologically active peptide applications in medicine have increased the need for new methods for peptide delivery. The...
Technological developments in the field of biologically active peptide applications in medicine have increased the need for new methods for peptide delivery. The disadvantage of peptides as drugs is their low biological stability. Recently, great attention has been paid to self-assembling peptides that can form fibrils. Such a formulation makes bioactive peptides more resistant to enzymatic degradation and druggable. Peptide fibrils can be carriers for peptides with interesting biological activities. These features open up prospects for using the peptide fibrils as long-acting drugs and are a valid alternative to conventional peptidic therapies. In our study, we designed new peptide scaffolds that are a hybrid of three interconnected amino acid sequences and are: pro-regenerative, cleavable by neutrophilic elastase, and fibril-forming. We intended to obtain peptides that are stable in the wound environment and that, when applied, would release a biologically active sequence. Our studies showed that the designed hybrid peptides show a high tendency toward regular fibril formation and are able to release the pro-regenerative sequence. Cytotoxicity studies showed that all the designed peptides were safe, did not cause cytotoxic effects and revealed a pro-regenerative potential in human fibroblast and keratinocyte cell lines. In vivo experiments in a dorsal skin injury model in mice indicated that two tested peptides moderately promote tissue repair in their free form. Our research proves that peptide fibrils can be a druggable form and a scaffold for active peptides.
Topics: Amino Acid Sequence; Animals; Cell Proliferation; Cell Survival; Chemical Phenomena; Drug Carriers; Fibroblasts; Humans; Keratinocytes; Mice; Microscopy, Atomic Force; Microscopy, Electron; Peptides; Proteolysis; Regenerative Medicine; Spectrum Analysis; Tissue Scaffolds; Wound Healing
PubMed: 33917000
DOI: 10.3390/ijms22083818 -
Journal of the American Chemical Society Dec 2023Rapid and efficient cyclization methods that form structurally novel peptidic macrocycles are of high importance for medicinal chemistry. Herein, we report the first...
Rapid and efficient cyclization methods that form structurally novel peptidic macrocycles are of high importance for medicinal chemistry. Herein, we report the first gold(I)-catalyzed macrocyclization of peptide-EBXs (ethynylbenziodoxolones) via C-Trp C-H activation. This reaction was carried out in the presence of protecting group free peptide sequences and is enabled by a simple commercial gold catalyst (AuCl·MeS). The method displayed a rapid reaction rate (within 10 min), wide functional group tolerance (27 unprotected peptides were cyclized), and up to 86% isolated yield. The obtained highly conjugated cyclic peptide linker, formed through C-H alkynylation, can be directly applied to live-cell imaging as a fluorescent probe without further attachment of fluorophores.
Topics: Peptides, Cyclic; Peptides; Amino Acid Sequence; Cyclization; Catalysis; Fluorescent Dyes
PubMed: 38035635
DOI: 10.1021/jacs.3c09261 -
Protein Science : a Publication of the... Jan 2020Molecular docking of peptides to proteins can be a useful tool in the exploration of the possible peptide binding sites and poses. CABS-dock is a method for...
Molecular docking of peptides to proteins can be a useful tool in the exploration of the possible peptide binding sites and poses. CABS-dock is a method for protein-peptide docking that features significant conformational flexibility of both the peptide and the protein molecules during the peptide search for a binding site. The CABS-dock has been made available as a web server and a standalone package. The web server is an easy to use tool with a simple web interface. The standalone package is a command-line program dedicated to professional users. It offers a number of advanced features, analysis tools and support for large-sized systems. In this article, we outline the current status of the CABS-dock method, its recent developments, applications, and challenges ahead.
Topics: Binding Sites; Computational Biology; Models, Molecular; Molecular Docking Simulation; Peptides; Protein Binding; Protein Conformation; Proteins; Software; User-Computer Interface; Web Browser
PubMed: 31682301
DOI: 10.1002/pro.3771 -
Current Opinion in Structural Biology Oct 2020Computational protein-protein docking is one of the most intensively studied topics in structural bioinformatics. The field has made substantial progress through over... (Review)
Review
Computational protein-protein docking is one of the most intensively studied topics in structural bioinformatics. The field has made substantial progress through over three decades of development. The development began with methods for rigid-body docking of two proteins, which have now been extended in different directions to cover the various macromolecular interactions observed in a cell. Here, we overview the recent developments of the variations of docking methods, including multiple protein docking, peptide-protein docking, and disordered protein docking methods.
Topics: Computational Biology; Macromolecular Substances; Molecular Docking Simulation; Peptides; Protein Binding; Proteins; Software
PubMed: 32599506
DOI: 10.1016/j.sbi.2020.05.017 -
Bioorganic & Medicinal Chemistry Jul 2022PP1 is a major phosphoserine/threonine-specific phosphatase that is involved in diseases such as heart insufficiency and diabetes. PP1-disrupting peptides (PDPs) are...
PP1 is a major phosphoserine/threonine-specific phosphatase that is involved in diseases such as heart insufficiency and diabetes. PP1-disrupting peptides (PDPs) are selective modulators of PP1 activity that release its catalytic subunit, which then dephosphorylates nearby substrates. Recently, PDPs enabled the creation of phosphatase-recruiting chimeras, which are bifunctional molecules that guide PP1 to a kinase to dephosphorylate and inactivate it. However, PDPs are 23mer peptides, which is not optimal for their use in therapy due to potential stability and immunogenicity issues. Therefore, we present here the sequence optimization of the 23mer PDP to a 5mer peptide, involving several attempts considering structure-based virtual screening, high throughput screening and peptide sequence optimization. We provide here a strong pharmacophore as lead structure to enable PP1 targeting in therapy or its use in phosphatase-recruiting chimeras in the future.
Topics: Amino Acid Sequence; Catalytic Domain; Peptides; Phosphorylation; Protein Phosphatase 1; Threonine
PubMed: 35525109
DOI: 10.1016/j.bmc.2022.116785 -
Biochemical Society Transactions Jun 2021Protein-protein interactions (PPIs) orchestrate nearly all biological processes. They are also considered attractive drug targets for treating many human diseases,... (Review)
Review
Protein-protein interactions (PPIs) orchestrate nearly all biological processes. They are also considered attractive drug targets for treating many human diseases, including cancers and neurodegenerative disorders. Protein-fragment complementation assays (PCAs) provide a direct and straightforward way to study PPIs in living cells or multicellular organisms. Importantly, PCAs can be used to detect the interaction of proteins expressed at endogenous levels in their native cellular environment. In this review, we present the principle of PCAs and discuss some of their advantages and limitations. We describe their application in large-scale experiments to investigate PPI networks and to screen or profile PPI targeting compounds.
Topics: Animals; Humans; Models, Molecular; Peptide Fragments; Peptides; Protein Binding; Protein Domains; Protein Interaction Mapping; Proteins; Proteome; Proteomics
PubMed: 34156434
DOI: 10.1042/BST20201058 -
Molecular Systems Biology Oct 2021Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually...
Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually inhibitory relationship between reduced glutathione and reactive oxygen species (ROS)-two opposing metabolites that are linked to upstream nutrient metabolic pathways (glucose, cysteine, and glutamine) and downstream feedback loops of signaling pathways (calcium and NADPH oxidase). We developed a nutrient-redox model of human cells to understand system-level properties of this network. Combining in silico modeling and ROS measurements in individual cells, we show that ROS dynamics follow a switch-like, all-or-none response upon glucose deprivation at a threshold that is approximately two orders of magnitude lower than its physiological concentration. We also confirm that this ROS switch can be irreversible and exhibits hysteresis, a hallmark of bistability. Our findings evidence that bistability modulates redox homeostasis in human cells and provide a general framework for quantitative investigations of redox regulation in humans.
Topics: Glutathione; Homeostasis; Humans; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction
PubMed: 34612597
DOI: 10.15252/msb.202110480 -
Molecules (Basel, Switzerland) Dec 2020Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands...
Peptide aptamers are short amino acid chains that are capable of binding specifically to ligands in the same way as their much larger counterparts, antibodies. Ligands of therapeutic interest that can be targeted are other peptide chains or loops located on the surface of protein receptors (e.g., GCPR), which take part in cell-to-cell communications either directly or via the intermediary of hormones or signalling molecules. To confer on aptamers the same sort of conformational rigidity that characterises an antibody binding site, aptamers are often constructed in the form of cyclic peptides, on the assumption that this will encourage stronger binding interactions than would occur if the aptamers were simply linear chains. However, no formal studies have been conducted to confirm the hypothesis that linear peptides will engage in stronger binding interactions with cyclic peptides than with other linear peptides. In this study, the interaction of a model cyclic decamer with a series of linear peptide constructs was compared with that of a linear peptide with the same sequence, showing that the cyclic configuration does confer benefits by increasing the strength of binding.
Topics: Amino Acids; Antibodies; Aptamers, Peptide; Binding Sites; Cell Communication; Hormones; Ligands; Molecular Conformation; Peptides; Peptides, Cyclic; Protein Binding; Signal Transduction
PubMed: 33371475
DOI: 10.3390/molecules25246055 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jun 2021Bioactive peptides play important roles in promoting human health, such as lowering blood pressure, blood sugar and blood lipid, anti-obesity, and anti-cancer. Thus,... (Review)
Review
Bioactive peptides play important roles in promoting human health, such as lowering blood pressure, blood sugar and blood lipid, anti-obesity, and anti-cancer. Thus, exploring functional bioactive peptides and developing efficient production technologies are of crucial importance. Herein, we review the development of function discovery and production technology for natural bioactive peptides. Presently, the top-down and bottom-up approaches are mainly used for the function discovery and production of natural active peptides. The top-down approach includes the direct extraction and identification for functional discovery, and the direct extraction, enzymatic hydrolysis and microbial fermentation for production. The bottom-up approach includes the polypeptide modification and database mining for functional discovery, and the chemical synthesis, enzyme synthesis, recombinant expression and cell-free synthesis for production. The top-down approach is usually associated with complicated process, lower efficiency, higher cost, harder quality control, and uncertain functionality, while the bottom-up approach is more suitable for the development of peptide drugs but difficult to be used for functional foods. With the technology development of sequencing and mass spectrometry, it is easier to obtain the proteomic information of various organisms at the molecular level. Based on the proteomic information, the top-down and bottom-up approaches can be combined to overcome the disadvantages of using these two approaches alone, thus providing a new strategy for the rapid development and production of natural active peptides.
Topics: Fermentation; Humans; Mass Spectrometry; Peptides; Proteomics; Technology
PubMed: 34227301
DOI: 10.13345/j.cjb.210047