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Cyclic and Lasso Peptides: Sequence Determination, Topology Analysis, and Rotaxane Formation.

ABSTRACT: A broadly applicable chemical cleavage methodology to facilitate MS/MS sequencing was developed for macrocyclic and lasso peptides, which hold promise as exciting new therapeutics. Existing methods such as Edman degradation, CNBr cleavage, and enzymatic digestion are either limited in scope or completely fail in cleavage of constrained nonribosomal peptides. Importantly, the new method was utilized for synthesizing a unique peptide-based rotaxane (both cyclic and threaded) from the lasso peptide, benenodin-1 ?C5.

SUBMITTER: Elashal HE

PROVIDER: S-EPMC6080247 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Cyclic and Lasso Peptides: Sequence Determination, Topology Analysis, and Rotaxane Formation.

Elashal Hader E HE Cohen Ryan D RD Elashal Heidi E HE Zong Chuhan C Link A James AJ Raj Monika M

Angewandte Chemie (International ed. in English) 20180427 21

A broadly applicable chemical cleavage methodology to facilitate MS/MS sequencing was developed for macrocyclic and lasso peptides, which hold promise as exciting new therapeutics. Existing methods such as Edman degradation, CNBr cleavage, and enzymatic digestion are either limited in scope or completely fail in cleavage of constrained nonribosomal peptides. Importantly, the new method was utilized for synthesizing a unique peptide-based rotaxane (both cyclic and threaded) from the lasso peptide ...[more]

PMID: 29645322

Similar Datasets

Lasso Peptide Benenodin-1 Is a Thermally Actuated [1]Rotaxane Switch.

Project description:Mechanically interlocked molecules that change their conformation in response to stimuli have been developed by synthetic chemists as building blocks for molecular machines. Here we describe a natural product, the lasso peptide benenodin-1, which exhibits conformational switching between two distinct threaded conformers upon actuation by heat. We have determined the structures of both conformers and have characterized the kinetics and energetics of the conformational switch. Single amino acid substitutions to benenodin-1 generate peptides that are biased to a single conformer, showing that the switching behavior is potentially an evolvable trait in these peptides. Lasso peptides such as benenodin-1 can be recognized and cleaved by enzymes called lasso peptide isopeptidases. We show that only the native conformer of benenodin-1 is cleaved by its cognate isopeptidase. Thus, thermally induced conformational switching of benenodin-1 may also be relevant to the biological function of these molecules.

| S-EPMC5576865 | biostudies-literature

Protein disulfide topology determination through the fusion of mass spectrometric analysis and sequence-based prediction using Dempster-Shafer theory.

Project description:BACKGROUND: Disulfide bonds constitute one of the most important cross-linkages in proteins and significantly influence protein structure and function. At the state-of-the-art, various methodological frameworks have been proposed for identification of disulfide bonds. These include among others, mass spectrometry-based methods, sequence-based predictive approaches, as well as techniques like crystallography and NMR. Each of these frameworks has its advantages and disadvantages in terms of pre-requisites for applicability, throughput, and accuracy. Furthermore, the results from different methods may concur or conflict in parts. RESULTS: In this paper, we propose a novel and theoretically rigorous framework for disulfide bond determination based on information fusion from different methods using an extended formulation of Dempster-Shafer theory. A key advantage of our approach is that it can automatically deal with concurring as well as conflicting evidence in a data-driven manner. Using the proposed framework, we have developed a method for disulfide bond determination that combines results from sequence-based prediction and mass spectrometric inference. This method leads to more accurate disulfide bond determination than any of the constituent methods taken individually. Furthermore, experiments indicate that the method improves the accuracy of bond identification as compared to leading extant methods at the state-of-the-art. Finally, the proposed framework is extensible in that results from any number of approaches can be incorporated. Results obtained using this framework can especially be useful in cases where the complexity of the bonding patterns coupled with specificities of the fragmentation pattern or limitations of computational models impair any single method to perform consistently across a diverse set of molecules.

| S-EPMC3549834 | biostudies-literature

Self-Assembly of Catenanes from Lasso Peptides.

Project description:Lasso peptides exist naturally in a threaded state as [1]rotaxanes, and we reasoned that lasso peptides cleaved in their loop region could serve as building blocks for catenanes. Mutagenesis of the lasso peptide microcin J25 (MccJ25) with two cysteine residues followed by cleavage of the peptide with trypsin led to a [2]rotaxane structure that self-assembled into a [3]catenane and [4]catenanes at room temperature in aqueous solution. The [3]catenane represents the smallest ring size of a catenane composed solely of polypeptide segments. The NMR structure of the [3]catenane was determined, suggesting that burial of hydrophobic residues may be a driving force for assembly of the catenane structure.

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Efficient delivery of cyclic peptides into mammalian cells with short sequence motifs.

Project description:Cyclic peptides hold great potential as therapeutic agents and research tools, but their broad application has been limited by poor membrane permeability. Here, we report a potentially general approach for intracellular delivery of cyclic peptides. Short peptide motifs rich in arginine and hydrophobic residues (e.g., F?RRRR, where ? is l-2-naphthylalanine), when embedded into small- to medium-sized cyclic peptides (7-13 amino acids), bound to the plasma membrane of mammalian cultured cells and were subsequently internalized by the cells. Confocal microscopy and a newly developed peptide internalization assay demonstrated that cyclic peptides containing these transporter motifs were translocated into the cytoplasm and nucleus at efficiencies 2-5-fold higher than that of nonaarginine (R(9)). Furthermore, incorporation of the F?RRRR motif into a cyclic peptide containing a phosphocoumaryl aminopropionic acid (pCAP) residue generated a cell permeable, fluorogenic probe for detecting intracellular protein tyrosine phosphatase activities.

| S-EPMC3574231 | biostudies-literature

Proteins involved in taking up cyclic peptides

Project description:To identify differentially expressed genes that dictates the cell uptake activity

2023-06-01 | GSE202764 | GEO

Cyclic Opioid Peptides.

Project description:For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.

| S-EPMC5693220 | biostudies-literature

Computational Insights into the Formation and Structure of S-N Containing Cyclic Peptides.

Project description:Cyclic peptides are known to have biologically important roles and may also be applicable to the pharmaceutical and other industries. Furthermore, thiols and amines, which are found throughout biological systems, can react to form S-N bonds and to date, ∼100 biomolecules containing such a bond have been identified. However, while there are in principle numerous S-N containing peptide-derived rings possible, only a few are presently known to occur in biochemical systems. Density functional theory-based calculations have been used to consider the formation and structure of S-N containing cyclic peptides from systematic series of linear peptides in which a cysteinyl has first been oxidized to a sulfenic or sulfonic acid. In addition, the possible effect of the cysteine's vicinal residue on the free energy of formation has also been considered. In general, when the cysteine is first oxidized to a sulfenic acid, only the formation of smaller S-N containing rings is calculated to be exergonic in aqueous solution. In contrast, when the cysteine is first oxidized to a sulfonic acid, the formation of all rings considered (with one exception) is calculated to be endergonic in aqueous solution. The nature of vicinal residue can influence ring formation through stabilizing or destabilizing intramolecular interactions.

| S-EPMC10210182 | biostudies-literature

Bioinformatics-guided discovery of biaryl-linked lasso peptides.

Project description:Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that feature an isopeptide bond and a distinct lariat fold. A growing number of secondary modifications have been described that further decorate lasso peptide scaffolds. Using genome mining, we have discovered a pair of lasso peptide biosynthetic gene clusters (BGCs) that include cytochrome P450 genes. Using mass spectrometry, stable isotope incorporation, and extensive 2D-NMR spectrometry, we report the structural characterization of two unique examples of (C-N) biaryl-linked lasso peptides. Nocapeptin A, from Nocardia terpenica, is tailored with a Trp-Tyr crosslink, while longipepetin A, from Longimycelium tulufanense, features a Trp-Trp linkage. Besides the unusual bicyclic frame, a Met of longipepetin A undergoes S-methylation to yield a trivalent sulfonium, a heretofore unprecedented RiPP modification. A bioinformatic survey revealed additional lasso peptide BGCs containing P450 enzymes which await future characterization. Lastly, nocapeptin A bioactivity was assessed against a panel of human and bacterial cell lines with modest growth-suppression activity detected towards Micrococcus luteus.

| S-EPMC10664482 | biostudies-literature

Lasso Peptides: Heterologous Production and Potential Medical Application.

Project description:Lasso peptides are natural products found in bacteria. They belong to a specific family of ribosomally-synthesized and posttranslationally-modified peptides with an unusual lasso structure. Lasso peptides possess remarkable thermal and proteolytic stability and various biological activities, such as antimicrobial activity, enzyme inhibition, receptor blocking, anticancer properties and HIV antagonism. They have promising potential therapeutic effects on gastrointestinal diseases, tuberculosis, Alzheimer's disease, cardiovascular disease, fungal infections and cancer. Lasso peptides with high stability have been shown to be good carriers for other bioactive peptides. These make them attractive candidates for pharmaceutical research. This review aimed to describe the strategies used for the heterologous production of lasso peptides. Also, it indicated their therapeutical potential and their capacity to use as an efficient scaffold for epitope grafting.

| S-EPMC7549694 | biostudies-literature

Attempting to synthesize lasso peptides using high pressure.

Project description:Lasso peptides are unique in that the tail of the lasso peptide threads through its macrolactam ring. The unusual structure and biological activity of lasso peptides have generated increased interest from the scientific community in recent years. Because of this, many new types of lasso peptides have been discovered. These peptides can be synthesized by microorganisms efficiently, and yet, their chemical assembly is challenging. Herein, we investigated the possibility of high pressure inducing the cyclization of linear precursors of lasso peptides. Unlike other molecules like rotaxanes which mechanically interlock at high pressure, the threaded lasso peptides did not form, even at pressures the high pressure up to 14 000 kbar.

| S-EPMC7314030 | biostudies-literature

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