Macrocyclic Peptides Closed by a Thioether–Bipyridyl Unit That Grants Cell Membrane Permeability
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PROVIDER: S-EPMC10591297 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:Inspired by the biosynthetic logic of lanthipeptide natural products, a new methodology was developed to direct the ribosomal synthesis of macrocyclic peptides constrained by an intramolecular thioether bond. As a first step, a robust and versatile strategy was implemented to enable the cyclization of ribosomally derived peptide sequences via a chemoselective reaction between a genetically encoded cysteine and a cysteine-reactive unnatural amino acid (O-(2-bromoethyl)-tyrosine). Combination of this approach with intein-catalyzed protein splicing furnished an efficient route to achieve the spontaneous, post-translational formation of structurally diverse macrocyclic peptides in bacterial cells. The present peptide cyclization strategy was also found to be amenable to integration with split intein-mediated circular ligation, resulting in the intracellular synthesis of conformationally constrained peptides featuring a bicyclic architecture.
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Project description:The biological activities and pharmacological properties of peptides and peptide mimetics are determined by their conformational states. Therefore, a detailed understanding of the conformational landscape is crucial for rational drug design. Nuclear magnetic resonance (NMR) is the only method for structure determination in solution. However, it remains challenging to determine the structures of peptides using NMR because of very weak nuclear Overhauser effects (NOEs), the semiquantitative nature of the rotating frame Overhauser effect (ROE), and the low number of NOEs/ROEs in N-methylated peptides. In this study, we introduce a new approach to investigating the structures of modified macrocyclic peptides. We utilize exact NOEs (eNOEs) in viscous solvent mixtures to replicate various cellular environments. eNOEs provide detailed structural information for highly dynamic modified peptides. Structures of high precision were obtained for cyclosporin A, with a backbone atom rmsd of 0.10 Å. Distinct conformational states in different environments were identified for omphalotin A (OmphA), a fungal nematotoxic and multiple backbone N-methylated macrocyclic peptides. A model for cell-permeation is presented for OmphA, based on its structures in polar, apolar, and mixed polarity solvents. During the transition from a polar to an apolar environment, OmphA undergoes a rearrangement of its H-bonding network, accompanied by a cis to trans isomerization of the ω torsion angle within a type VIa β-turn. We hypothesize that the kinetics of these conformational transitions play a crucial role in determining the membrane-permeation capabilities of OmphA.
| S-EPMC10739998 | biostudies-literature
Project description:Solvent shielding of the amide hydrogen bond donor (NH groups) through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. We demonstrate that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor (>C = O) through a thioamide substitution (>C = S). The membrane permeability is a consequence of the lower desolvation penalty of the macrocycle resulting from a concerted effect of conformational restriction, local desolvation of the thioamide bond, and solvent shielding of the amide NH groups. The enhanced permeability and metabolic stability on thioamidation improve the bioavailability of a macrocyclic peptide composed of hydrophobic amino acids when administered through the oral route in rats. Thioamidation of a bioactive macrocyclic peptide composed of polar amino acids results in analogs with longer duration of action in rats when delivered subcutaneously. These results highlight the potential of O to S substitution as a stable backbone modification in improving the pharmacological properties of peptide macrocycles.
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Project description:The effort to modulate challenging protein targets has stimulated interest in ligands that are larger and more complex than typical small-molecule drugs. While combinatorial techniques such as mRNA display routinely produce high-affinity macrocyclic peptides against classically undruggable targets, poor membrane permeability has limited their use toward primarily extracellular targets. Understanding the passive membrane permeability of macrocyclic peptides would, in principle, improve our ability to design libraries whose leads can be more readily optimized against intracellular targets. Here, we investigate the permeabilities of over 200 macrocyclic 10-mers using the thioether cyclization motif commonly found in mRNA display macrocycle libraries. We identified the optimal lipophilicity range for achieving permeability in thioether-cyclized 10-mer cyclic peptide-peptoid hybrid scaffolds and showed that permeability could be maintained upon extensive permutation in the backbone. In one case, changing a single amino acid from d-Pro to d-NMe-Ala, representing the loss of a single methylene group in the side chain, resulted in a highly permeable scaffold in which the low-dielectric conformation shifted from the canonical cross-beta geometry of the parent compounds into a novel saddle-shaped fold in which all four backbone NH groups were sequestered from the solvent. This work provides an example by which pre-existing physicochemical knowledge of a scaffold can benefit the design of macrocyclic peptide mRNA display libraries, pointing toward an approach for biasing libraries toward permeability by design. Moreover, the compounds described herein are a further demonstration that geometrically diverse, highly permeable scaffolds exist well beyond conventional drug-like chemical space.
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Project description:Recycling of receptors from the endosomal recycling compartment to the plasma membrane is a critical cellular process, and recycling is particularly important for maintaining invasiveness in solid tumors. In this work, we continue our efforts to inhibit EHD1, a critical adaptor protein involved in receptor recycling. We applied a diversity-oriented macrocyclization approach to produce cyclic peptides with varied conformations, but that each contain a motif that binds to the EH domain of EHD1. Screening these uncovered several new inhibitors for EHD1's EH domain, the most potent of which bound with a Kd of 3.1μM. Several of the most potent inhibitors were tested in a cellular assay that measures extent of vesicle recycling. Inhibiting EHD1 could potentially slow cancer invasiveness and metastasis, and these cyclic peptides represent the most potent inhibitors of EHD1 to date.
| S-EPMC5844793 | biostudies-literature
Project description:Thioether containing peptides were obtained following three synthetic routes. In route A, halo acids esterified on 2-chlorotrityl(Cltr) resin were reacted with N-fluorenylmethoxycarbonyl (Fmoc) aminothiols. These were either cleaved from the resin to the corresponding (Fmoc-aminothiol)carboxylic acids, which were used as key building blocks in solid phase peptide synthesis (SPPS), or the N-Fmoc group was deprotected and peptide chains were elongated by standard SPPS. The obtained N-Fmoc protected thioether containing peptides were then condensed either in solution, or on solid support, with the appropriate amino components of peptides. In route B, the thioether containing peptides were obtained by the reaction of N-Fmoc aminothiols with bromoacetylated peptides, which were synthesized on Cltr-resin, followed by removal of the N-Fmoc group and subsequent peptide elongation by standard SPPS. In route C, the thioether containing peptides were obtained by the condensation of a haloacylated peptide synthesized on Cltr-resin and a thiol-peptide synthesized either on 4-methoxytrityl(Mmt) or trityl(Trt) resin.
| S-EPMC6983143 | biostudies-literature
Project description:The bis-ortho-thioether 9,10-bis[(o-methylthio)phenyl]anthracene was synthesized as a syn-atropisomer, as revealed by X-ray diffraction. This alkylaryl thioether ligand (L) formed different macrocyclic complexes by coordination with silver(I) salts depending on the nature of the anion: M2L2 for AgOTf and AgOTFA, M6L4 for AgNO3. A discrete M2L complex was obtained in the presence of bulky PPh3AgOTf. These silver(I) complexes adopted similar structures in solution and in the solid state. As each sulfur atom in the ligand is prochiral, macrocycles L2M2 were obtained as mixtures of diastereoisomers, depending on the configurations of the sulfur atoms coordinated to silver cations. The X-ray structures of the two L2·(AgOTf)2 stereoisomers highlighted their different geometry. The catalytic activity of all silver(I) complexes was effective under homogeneous conditions in two tandem addition/cycloisomerization of alkynes using 0.5-1 mol % of catalytic loading.
| S-EPMC6808213 | biostudies-literature
Project description:Recently, cyclic peptides have been considered breakthrough drugs because they can interact with "undruggable" targets such as intracellular protein-protein interactions. Membrane permeability is an essential indicator of oral bioavailability and intracellular targeting, and the development of membrane-permeable peptides is a bottleneck in cyclic peptide drug discovery. Although many experimental data on membrane permeability of cyclic peptides have been reported, a comprehensive database is not yet available. A comprehensive membrane permeability database is essential for developing computational methods for cyclic peptide drug design. In this study, we constructed CycPeptMPDB, the first web-accessible database of cyclic peptide membrane permeability. We collected information on a total of 7334 cyclic peptides, including the structure and experimentally measured membrane permeability, from 45 published papers and 2 patents from pharmaceutical companies. To unambiguously represent cyclic peptides larger than small molecules, we used the hierarchical editing language for macromolecules notation to generate a uniform sequence representation of peptides. In addition to data storage, CycPeptMPDB provides several supporting functions such as online data visualization, data analysis, and downloading. CycPeptMPDB is expected to be a valuable platform to support membrane permeability research on cyclic peptides. CycPeptMPDB can be freely accessed at http://cycpeptmpdb.com.
| S-EPMC10091415 | biostudies-literature
Project description:BackgroundBasic cell-penetrating peptides are potential vectors for therapeutic molecules and display antimicrobial activity. The peptide-membrane contact is the first step of the sequential processes leading to peptide internalization and cell activity. However, the molecular mechanisms involved in peptide-membrane interaction are not well understood and are frequently controversial. Herein, we compared the membrane activities of six basic peptides with different size, charge density and amphipaticity: Two cell-penetrating peptides (penetratin and R9), three amphipathic peptides and the neuromodulator substance P.Methodology/principal findingsExperiments of X ray diffraction, video-microscopy of giant vesicles, fluorescence spectroscopy, turbidimetry and calcein leakage from large vesicles are reported. Permeability and toxicity experiments were performed on cultured cells. The peptides showed differences in bilayer thickness perturbations, vesicles aggregation and local bending properties which form lipidic tubular structures. These structures invade the vesicle lumen in the absence of exogenous energy.Conclusions/significanceWe showed that the degree of membrane permeabilization with amphipathic peptides is dependent on both peptide size and hydrophobic nature of the residues. We propose a model for peptide-induced membrane perturbations that explains the differences in peptide membrane activities and suggests the existence of a facilitated "physical endocytosis," which represents a new pathway for peptide cellular internalization.
| S-EPMC1790702 | biostudies-literature
Project description:Being able to effectively target RNA with potent ligands will open up a large number of potential therapeutic options. The knowledge on how to achieve this is ever expanding but an important question that remains open is what chemical matter is suitable to achieve this goal. The high flexibility of an RNA as well as its more limited chemical diversity and featureless binding sites can be difficult to target selectively but can be addressed by well-designed cyclic peptides. In this review we will provide an overview of reported cyclic peptide ligands for therapeutically relevant RNA targets and discuss the methods used to discover them. We will also provide critical insights into the properties required for potent and selective interaction and suggestions on how to assess these parameters. The use of cyclic peptides to target RNA is still in its infancy but the lessons learned from past examples can be adopted for the development of novel potent and selective ligands.
| S-EPMC9062085 | biostudies-literature