Aromatic carbohydrate amphiphile disrupts cancer spheroids and prevents relapse.
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ABSTRACT:
SUBMITTER: Brito A
PROVIDER: S-EPMC7541621 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Protein-carbohydrate interactions play pivotal roles in health and disease. However, defining and manipulating these interactions has been hindered by an incomplete understanding of the underlying fundamental forces. To elucidate common and discriminating features in carbohydrate recognition, we have analyzed quantitatively X-ray crystal structures of proteins with noncovalently bound carbohydrates. Within the carbohydrate-binding pockets, aliphatic hydrophobic residues are disfavored, whereas aromatic side chains are enriched. The greatest preference is for tryptophan with an increased prevalence of 9-fold. Variations in the spatial orientation of amino acids around different monosaccharides indicate specific carbohydrate C-H bonds interact preferentially with aromatic residues. These preferences are consistent with the electronic properties of both the carbohydrate C-H bonds and the aromatic residues. Those carbohydrates that present patches of electropositive saccharide C-H bonds engage more often in CH-π interactions involving electron-rich aromatic partners. These electronic effects are also manifested when carbohydrate-aromatic interactions are monitored in solution: NMR analysis indicates that indole favorably binds to electron-poor C-H bonds of model carbohydrates, and a clear linear free energy relationships with substituted indoles supports the importance of complementary electronic effects in driving protein-carbohydrate interactions. Together, our data indicate that electrostatic and electronic complementarity between carbohydrates and aromatic residues play key roles in driving protein-carbohydrate complexation. Moreover, these weak noncovalent interactions influence which saccharide residues bind to proteins, and how they are positioned within carbohydrate-binding sites.
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Project description:We designed multiblock amphiphiles AmF and AmH, which consist of perfluorinated and non-fluorinated hydrophobic units, respectively. Absorption spectroscopy revealed that both amphiphiles are molecularly dispersed in organic solvent, while they form aggregates under aqueous conditions. Furthermore, we investigated whether AmF and AmH can be incorporated into DOPC lipid bilayer membranes, and found that the maximum concentration of AmF that can be incorporated into DOPC lipid bilayer membranes is 43 times higher than that of AmH.
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Project description:Controlled release is an essential requirement for delivery of hydrogen sulfide (H2S) because of its reactive nature, short half-life in biological fluids, and toxicity at high concentrations. In this context, H2S delivery via hydrogels may be beneficial as they can deliver H2S locally at the site of interest. Herein, we employed hydrogels based on aromatic peptide amphiphiles (APAs) with tunable mechanical properties to modulate the rates of H2S release. The APAs contained an aromatic S-aroylthiooxime (SATO) H2S donor attached with a linker to a short IAVEEE hexapeptide. Linker units included carbonyl, substituted O-methylenes, alkenyl, and alkyl segments with the goal of evaluating the role of linker structure on self-assembly, capacity for hydrogelation, and H2S release rate. We studied each peptide by transmission electron microscopy, circular dichroism spectroscopy, and rheology, and we measured H2S release rates from each gel, triggering SATO decomposition and release of H2S by addition of cysteine (Cys). Using an H2S-selective electrode probe as well as a turn-on fluorescent H2S probe in the presence of H9C2 cardiomyocytes, we found that the rate of H2S release from the hydrogels depended on the rate of Cys penetration into the nanofiber core with stiffer gels showing longer overall release.
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Project description:Interactions between proteins and carbohydrates are ubiquitous in biology. Therefore, understanding the factors that determine their affinity and selectivity are correspondingly important. Herein, we have determined the relative strengths of intramolecular interactions between a series of monosaccharides and an aromatic ring close to the glycosylation site in an N-glycoprotein host. We employed the enhanced aromatic sequon, a structural motif found in the reverse turns of some N-glycoproteins, to facilitate face-to-face monosaccharide-aromatic interactions. A protein host was used because the dependence of the folding energetics on the identity of the monosaccharide can be accurately measured to assess the strength of the carbohydrate-aromatic interaction. Our data demonstrate that the carbohydrate-aromatic interaction strengths are moderately affected by changes in the stereochemistry and identity of the substituents on the pyranose rings of the sugars. Galactose seems to make the weakest and allose the strongest sugar-aromatic interactions, with glucose, N-acetylglucosamine (GlcNAc) and mannose in between. The NMR solution structures of several of the monosaccharide-containing N-glycoproteins were solved to further understand the origins of the similarities and differences between the monosaccharide-aromatic interaction energies. Peracetylation of the monosaccharides substantially increases the strength of the sugar-aromatic interaction in the context of our N-glycoprotein host. Finally, we discuss our results in light of recent literature regarding the contribution of electrostatics to CH-π interactions and speculate on what our observations imply about the absolute conservation of GlcNAc as the monosaccharide through which N-linked glycans are attached to glycoproteins in eukaryotes.
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Project description:Despite the great progress in the field of drug delivery systems for cancer treatment over the last decade, many challenges still lie ahead, such as low drug loading, deep penetration of tumors, side effects, and the development of drug resistance. A class of cationic membrane lytic peptides has shown potential as an anticancer agent by inducing cancer cell death via membrane disruption; meanwhile, their intrinsic selectivity renders them as having low cytotoxicity towards noncancerous cells. Here, we report the use of a cationic peptide amphiphile (PA), named PAH6, to load doxorubicin (Dox) that is intercalated in an ATP-binding aptamer-incorporated DNA scaffold. The PA contains a cationic lytic sequence, (KLAKLAK)₂, a polyhistidine segment for the "proton sponge" effect, and a hydrophobic alkyl tail to drive the self-assembly. Dox-loaded DNA was found to form a spherical nanocomplex (NC) with PAH6 with particle sizes below 100 nm at various ratios. Since the carrier PAH6 is also a therapeutic agent, the drug loadings of the NC reached up to ~86% within the ratios we tested, and Dox was released from the NC in an ATP-rich environment. In vitro studies indicate that the presence of PAH6 could permeabilize cell membranes and kill cells through fast membrane disruption and depolarization of mitochondrial membranes. The cytotoxicity tests were conducted using A549 nonsmall cell lung cancer cells and NIH-3T3 fibroblast cells. PAH6 showed selectivity towards A549 cells. Significantly, the Dox-DNA/PAH6 NC exhibited a synergistic effect against A549 cells, with the IC50 decreased up to ~90% for Dox and ~69% for PAH6 when compared to the IC50 values of the two components, respectively. Furthermore, the selectivity of PAH6 conferred to the complex an improved therapeutic index between A549 and NIH-3T3 cells. A 3D-cultured A549 spheroid model was adopted to test the capability of Dox-DNA/PAH6 for tumor penetration. The PAH6 or Dox-DNA/PAH6 complex was found to break the spheroids into pieces, while Dox-treated spheroids maintained their shapes. In summary, this work provides a new strategy for constructing nanomedicines using therapeutic agents to meet the features required by anticancer treatment.
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Project description:Plant cell walls constitute the majority of lignocellulosic biomass and serve as a renewable resource of biomaterials and biofuel. Extensive interactions between polysaccharides and the aromatic polymer lignin make lignocellulose recalcitrant to enzymatic hydrolysis, but this polymer network remains poorly understood. Here we interrogate the nanoscale assembly of lignocellulosic components in plant stems using solid-state nuclear magnetic resonance and dynamic nuclear polarization approaches. We show that the extent of glycan-aromatic association increases sequentially across grasses, hardwoods, and softwoods. Lignin principally packs with the xylan in a non-flat conformation via non-covalent interactions and partially binds the junction of flat-ribbon xylan and cellulose surface as a secondary site. All molecules are homogeneously mixed in softwoods; this unique feature enables water retention even around the hydrophobic aromatics. These findings unveil the principles of polymer interactions underlying the heterogeneous architecture of lignocellulose, which may guide the rational design of more digestible plants and more efficient biomass-conversion pathways.
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Project description:H2S is a gasotransmitter with several physiological roles, but its reactivity and short half-life in biological media make its controlled delivery difficult. For biological applications of the gas, hydrogels have the potential to deliver H2S with several advantages over other donor systems, including localized delivery, controlled release rates, biodegradation, and variable mechanical properties. In this study, we designed and evaluated peptide-based H2S-releasing hydrogels with controllable H2S delivery. The hydrogels were prepared from short, self-assembling aromatic peptide amphiphiles (APAs), functionalized on their N-terminus with S-aroylthiooximes (SATOs), which release H2S in response to a thiol trigger. The APAs were studied both in solution and in gel forms, with gelation initiated by addition of CaCl2. Various substituents were included on the SATO component of the APAs in order to evaluate their effects on self-assembled morphology and H2S release rate in both the solution and gel phases. Transmission electron microscopy (TEM) images confirmed that all H2S-releasing APAs self-assembled into nanofibers above a critical aggregation concentration (CAC) of ∼0.5 mg/mL. Below the CAC, substituents on the SATO group affected H2S release rates predictably in line with electronic effects (Hammett σ values) according to a linear free energy relationship. Above the CAC, circular dichroism, infrared, and fluorescence spectroscopies demonstrated that substituents influenced the self-assembled structures by affecting hydrogen bonding (β-sheet formation) and π-π stacking. At these concentrations, electronic control over release rates diminished, both in solution and in the gel form. Rather, the release rate depended primarily on the degree of organization in the β-sheets and the amount of π-π stacking. This supramolecular control over release rate may enable the evaluation of H2S-releasing hydrogels with different release rates in biological applications.
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Project description:In breast cancer (BC) patients, local recurrences often arise in proximity of the surgical scar, suggesting that response to surgery may have a causative role. Radiotherapy (RT) after lumpectomy significantly reduces the risk of recurrence. We investigated the direct effects of surgery and of RT delivered intraoperatively (IORT), by collecting irradiated and non-irradiated breast tissues from BC patients, after tumor removal. These breast tissue specimens have been profiled for their microRNA (miR) expression, in search of differentially expressed miR among patients treated or not with IORT. Our results demonstrate that IORT elicits effects that go beyond the direct killing of residual tumor cells. IORT altered the wound response, inducing the expression of miR-223 in the peri-tumoral breast tissue. miR-223 downregulated the local expression of epidermal growth factor (EGF), leading to decreased activation of EGF receptor (EGFR) on target cells and, eventually, dampening a positive EGF-EGFR autocrine/paracrine stimulation loop induced by the post-surgical wound-healing response. Accordingly, both RT-induced miR-223 and peri-operative inhibition of EGFR efficiently prevented BC cell growth and reduced recurrence formation in mouse models of BC. Our study uncovers unknown effects of RT delivered on a wounded tissue and prompts to the use of anti-EGFR treatments, in a peri-operative treatment schedule, aimed to timely treat BC patients and restrain recurrence formation.
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Project description:Relapse to drug abuse is often caused by exposure to drug-associated cues that evoke craving. Therefore, disruption of the cue-drug memory can prevent relapse. Memories destabilize and become temporarily labile upon their retrieval, and re-stabilize in a process termed reconsolidation. Pharmacological disruption of reconsolidation prevents relapse in animal models, yet may evoke side effects. Therefore, behavioral procedures capable of preventing cue-induced craving and relapse are extremely valuable. Aversion therapies, in which drug-paired cues are re-associated (counterconditioned) with aversive consequences, have limited success, because the previous cue-drug memory may recover, triggering relapse. Here, we prevented the memory recovery and relapse to cocaine seeking by applying aversive counterconditioning during memory reconsolidation. Mice were trained to seek cocaine in a conditioned place preference procedure. The cocaine-associated compartment was then counterconditioned with lithium chloride (LiCl)-induced malaise, preceded by a brief exposure to the compartment (memory retrieval). Relapse was assessed in a reinstatement test. We found that aversive counterconditioning conducted shortly after memory retrieval (during reconsolidation) induced a long-lasting prevention of relapse to cocaine seeking. However, mice relapsed when counterconditioned without, before, or long after memory retrieval, or when receiving LiCl without place counterconditioning. Our findings suggest that post-retrieval aversive counterconditioning leads to relapse prevention, possibly by replacing the cue-drug with a cue-aversion memory, thereby the cue ceases to evoke craving. Moreover, we found that a similar memory replacement procedure prevented relapse of conditioned place aversion. Hence, this novel procedure can also prevent relapse of aversive memories, providing a safe approach to alter various maladaptive behaviors.
| S-EPMC5240172 | biostudies-literature
Project description:We report on aromatic N-glucosides that inhibit selectively the cancer metabolism via two coexistent mechanisms: by initial deprivation of the glucose uptake through competitive binding in the glucose binding pocket of GLUT1 and by formation of a sequestering nanoscale supramolecular network at the cell surface through localized (biocatalytic) self-assembly. We demonstrate that the expression of the cancer associated GLUT1 and alkaline phosphatase are crucial for the effectiveness of this combined approach: cancer cells that overexpress both proteins are prompter to cell death when compared to GLUT1 overexpressing cells. Overall, we showcase that the synergism between physical and biochemical deprivation of cancer metabolism is a powerful approach for development of effective anticancer therapies.
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