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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 -
Chemical Society Reviews Jul 2023Unnatural helical peptidic foldamers have attracted considerable attention owing to their unique folding behaviours, diverse artificial protein binding mechanisms, and... (Review)
Review
Unnatural helical peptidic foldamers have attracted considerable attention owing to their unique folding behaviours, diverse artificial protein binding mechanisms, and promising applications in chemical, biological, medical, and material fields. Unlike the conventional α-helix consisting of molecular entities of native α-amino acids, unnatural helical peptidic foldamers are generally comprised of well-defined backbone conformers with unique and unnatural structural parameters. Their folded structures usually arise from unnatural amino acids such as -substituted glycine, -substituted-β-alanine, β-amino acid, urea, thiourea, α-aminoxy acid, α-aminoisobutyric acid, aza-amino acid, aromatic amide, γ-amino acid, as well as sulfono-γ-AA amino acid. They can exhibit intriguing and predictable three-dimensional helical structures, generally featuring superior resistance to proteolytic degradation, enhanced bioavailability, and improved chemodiversity, and are promising in mimicking helical segments of various proteins. Although it is impossible to include every piece of research work, we attempt to highlight the research progress in the past 10 years in exploring unnatural peptidic foldamers as protein helical segment mimics, by giving some representative examples and discussing the current challenges and future perspectives. We expect that this review will help elucidate the principles of structural design and applications of existing unnatural helical peptidic foldamers in protein segment mimicry, thereby attracting more researchers to explore and generate novel unnatural peptidic foldamers with unique structural and functional properties, leading to more unprecedented and practical applications.
Topics: Acids; Amides; Amino Acids; Peptides; Proteins; Aminoisobutyric Acids
PubMed: 37401344
DOI: 10.1039/d2cs00395c -
Clinical Chemistry Mar 2022Accurate discovery assay workflows are critical for identifying authentic circulating protein biomarkers in diverse blood matrices. Maximizing the commonalities in the...
BACKGROUND
Accurate discovery assay workflows are critical for identifying authentic circulating protein biomarkers in diverse blood matrices. Maximizing the commonalities in the proteomic workflows between different biofluids simplifies the approach and increases the likelihood for reproducibility. We developed a workflow that can accommodate 3 blood-based proteomes: naive plasma, depleted plasma and dried blood.
METHODS
Optimal conditions for sample preparation and data independent acquisition-mass spectrometry analysis were established in plasma then automated for depleted plasma and dried blood. The mass spectrometry workflow was modified to facilitate sensitive high-throughput analysis or deeper profiling with mid-throughput analysis. Analytical performance was evaluated by the linear response of peptides and proteins to a 6- or 7-point dilution curve and the reproducibility of the relative peptide and protein intensity for 5 digestion replicates per day on 3 different days for each biofluid.
RESULTS
Using the high-throughput workflow, 74% (plasma), 93% (depleted), and 87% (dried blood) displayed an inter-day CV <30%. The mid-throughput workflow had 67% (plasma), 90% (depleted), and 78% (dried blood) of peptides display an inter-day CV <30%. Lower limits of detection and quantification were determined for peptides and proteins observed in each biofluid and workflow. Based on each protein and peptide's analytical performance, we could describe the observable, reliable, reproducible, and quantifiable proteomes for each biofluid and workflow.
CONCLUSION
The standardized workflows established here allows for reproducible and quantifiable detection of proteins covering a broad dynamic range. We envisage that implementation of this standard workflow should simplify discovery approaches and facilitate the translation of candidate markers into clinical use.
Topics: Biomarkers; Blood; Humans; Peptides; Proteomics; Reproducibility of Results; Workflow
PubMed: 34687543
DOI: 10.1093/clinchem/hvab202 -
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 Peptide Science : An... Jul 2019In light of the 2018 Max Bergmann Medal, this review discusses advancements on chemical biology-driven templated chemistry developed in the author's laboratories. The... (Review)
Review
In light of the 2018 Max Bergmann Medal, this review discusses advancements on chemical biology-driven templated chemistry developed in the author's laboratories. The focused review introduces the template categories applied to orient functional units such as functional groups, chromophores, biomolecules, or ligands in space. Unimolecular templates applied in protein synthesis facilitate fragment coupling of unprotected peptides. Templating via bimolecular assemblies provides control over proximity relationships between functional units of two molecules. As an instructive example, the coiled coil peptide-templated labelling of receptor proteins on live cells will be shown. Termolecular assemblies provide the opportunity to put the proximity of functional units on two (bio)molecules under the control of a third party molecule. This allows the design of conditional bimolecular reactions. A notable example is DNA/RNA-triggered peptide synthesis. The last section shows how termolecular and multimolecular assemblies can be used to better characterize and understand multivalent protein-ligand interactions.
Topics: DNA; HEK293 Cells; Humans; Ligands; Molecular Structure; Peptides; Proteins; RNA
PubMed: 31309674
DOI: 10.1002/psc.3198 -
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 -
Briefings in Bioinformatics May 2024With their diverse biological activities, peptides are promising candidates for therapeutic applications, showing antimicrobial, antitumour and hormonal signalling... (Review)
Review
With their diverse biological activities, peptides are promising candidates for therapeutic applications, showing antimicrobial, antitumour and hormonal signalling capabilities. Despite their advantages, therapeutic peptides face challenges such as short half-life, limited oral bioavailability and susceptibility to plasma degradation. The rise of computational tools and artificial intelligence (AI) in peptide research has spurred the development of advanced methodologies and databases that are pivotal in the exploration of these complex macromolecules. This perspective delves into integrating AI in peptide development, encompassing classifier methods, predictive systems and the avant-garde design facilitated by deep-generative models like generative adversarial networks and variational autoencoders. There are still challenges, such as the need for processing optimization and careful validation of predictive models. This work outlines traditional strategies for machine learning model construction and training techniques and proposes a comprehensive AI-assisted peptide design and validation pipeline. The evolving landscape of peptide design using AI is emphasized, showcasing the practicality of these methods in expediting the development and discovery of novel peptides within the context of peptide-based drug discovery.
Topics: Artificial Intelligence; Peptides; Drug Discovery; Humans; Drug Design; Machine Learning; Computational Biology
PubMed: 38856172
DOI: 10.1093/bib/bbae275 -
Pediatric Endocrinology, Diabetes, and... 2015C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion... (Review)
Review
C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to different requirements in the treatment of diabetes. An important clinical role of C-peptide is differentiating between type 1 and type 2 diabetes. Low basal C-peptide can be considered as criterion for transferring the patients, initially diagnosed as type 2 diabetes, in the type 1 diabetes group. C-peptide level may be a good predictor of the clinical partial remission during the first year of type 1 diabetes. Latent autoimmune diabetes in adults (LADA) is a special form of diabetes that is clinically similar to type 2 diabetes but with positivity for pancreatic autoantibodies and lower C-peptide levels. The measurement of C-peptide level and of immunological markers may represent important additional tools for establishing the correct diagnosis. The natural course of these patients shows that C-peptide will decrease with time in parallel with the curve for C-peptide in classical type 1 diabetic patients. Persistence of C-peptide is an important clinical feature of MODY. It is particularly important to identify these patients as they are commonly misdiagnosed as type 1 diabetes and treated with insulin, C-peptide can be used to assist in patient selection for islet cell transplantation and post-transplant monitoring. High uncorrected fasting C-peptid in the presence of hyperglycemia may suggest insulin resistance.
Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion
PubMed: 26615015
DOI: 10.18544/PEDM-20.02.0004 -
Journal of Chemical Information and... Oct 2023Receptor-selective peptides are widely used as smart carriers for specific tumor-targeted delivery. A remarkable example is the cyclic nonapeptide RGD (CRGDKPGDC, ) that...
Receptor-selective peptides are widely used as smart carriers for specific tumor-targeted delivery. A remarkable example is the cyclic nonapeptide RGD (CRGDKPGDC, ) that couples intrinsic cytotoxic effects with striking tumor-homing properties. These peculiar features are based on a rather complex multistep mechanism of action, where the primary event is the recognition of RGD integrins. Despite the high number of preclinical studies and the recent success of a phase I trial for the treatment of pancreatic ductal adenocarcinoma (PDAC), there is little information available about the RGD three-dimensional (3D) structure and integrin binding properties. Here, we re-evaluate the peptide's affinity for cancer-related integrins including not only the previously known targets αvβ3 and αvβ5 but also the αvβ6 isoform, which is known to drive cell growth, migration, and invasion in many malignancies including PDAC. Furthermore, we use parallel tempering in the well-tempered ensemble (PT-WTE) metadynamics simulations to characterize the in-solution conformation of RGD and extensive molecular dynamics calculations to fully investigate its binding mechanism to integrin partners. Finally, we provide clues for fine-tuning the peptide's potency and selectivity profile, which, in turn, may further improve its tumor-homing properties.
Topics: Integrins; Cell Line, Tumor; Oligopeptides; Peptides; Pancreatic Neoplasms
PubMed: 37788340
DOI: 10.1021/acs.jcim.3c01071 -
International Journal of Nanomedicine 2020Metabolic syndrome comprises a cluster of comorbidities that represent a major risk of developing chronic diseases, such as type II diabetes, cardiovascular diseases,... (Review)
Review
Metabolic syndrome comprises a cluster of comorbidities that represent a major risk of developing chronic diseases, such as type II diabetes, cardiovascular diseases, and stroke. Alarmingly, metabolic syndrome reaches epidemic proportions worldwide. Today, lifestyle changes and multiple drug-based therapies represent the gold standard to address metabolic syndrome. However, such approaches face two major limitations: complicated drug therapeutic regimes, which in most cases could lead to patient incompliance, and limited drug efficacy. This has encouraged scientists to search for novel routes to deal with metabolic syndrome and related diseases. Within such approaches, self-assembled peptide formulations have emerged as a promising alternative for treating metabolic syndrome. In particular, self-assembled peptide hydrogels, either as acellular or cell-load three-dimensional scaffoldings have reached significant relevance in the biomedical field to prevent and restore euglycemia, as well as for controlling cardiovascular diseases and obesity. This has been possible thanks to the physicochemical tunability of peptides, which are developed from a chemical toolbox of versatile amino acids enabling flexibility of designing a wide range of self-assembled/co-assembled nanostructures forming biocompatible viscoelastic hydrogels. Peptide hydrogels can be combined with several biological entities, such as extracellular matrix proteins, drugs or cells, forming functional biologics with therapeutic ability for treatment of metabolic syndrome-comorbidities. Additionally, self-assembly peptides combine safety, tolerability, and effectivity attributes; by this presenting a promising platform for the development of novel pharmaceuticals capable of addressing unmet therapeutic needs for diabetes, cardiovascular disorders and obesity. In this review, recent advances in developing self-assembly peptide nanostructures tailored for improving treatment of metabolic syndrome and related diseases will be discussed from basic research to preclinical research studies. Challenges facing the development of approved medicinal products based on self-assembling peptide nanomaterials will be discussed in light of regulatory requirement for clinical authorization.
Topics: Animals; Humans; Hydrogels; Metabolic Syndrome; Nanostructures; Peptides
PubMed: 33376325
DOI: 10.2147/IJN.S278189