RESUMO
Chemical modifications of native peptides have significantly advanced modern drug discovery in recent decades. On this front, the installation of multitasking molecular grafts onto macrocyclic peptides offers numerous opportunities in biomedical applications. Here, we showcase a new class of borono-cyclic peptides featuring an azaborolo thiazolidine (ABT) graft, which can be readily assembled utilizing a bis-electrophilic boronic acid lynchpin while harnessing the inherent reactivity difference (>103 M-1 s-1) between the N-terminal cysteine and backbone cysteine for rapid and highly regioselective macrocyclization (â¼1 h) under physiological conditions. The ABT-crosslinked peptides are fairly stable in endogenous environments, but can provide the linear diazaborine peptides via treatment with α-nucleophiles. This efficient peptide crosslinking protocol was further extended for regioselective bicyclizations and engineering of α-helical structures. Finally, ABT-grafted peptides were exploited in biorthogonal conjugation, leading to highly effective intracellular delivery of an apoptotic peptide (KLA) in cancer cells. The mechanism of action by which ABT-grafted KLA peptide induces apoptosis was also explored.
RESUMO
Self-assembly provides access to non-covalently synthesized supramolecular materials with distinct properties from a single building block. However, dynamic switching between functional states still remains challenging, but holds enormous potential in material chemistry to design smart materials. Herein, we demonstrate a chemical fuel-mediated strategy to dynamically switch between two distinctly emissive aggregates, originating from the self-assembly of a naphthalimide-appended peptide building block. A molecularly dissolved building block shows very weak blue emission, whereas, in the assembled state (Agg-1), it shows cyan emission through π stacking-mediated excimer emission. The addition of a chemical fuel, ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC), converts the terminal aspartic acid present in the building block to an intra-molecularly cyclized anhydride in situ forming a second aggregated state, Agg-2, by changing the molecular packing, thereby transforming the emission to strong blue. Interestingly, the anhydride gets hydrolyzed gradually to reform Agg-1 and the initial cyan emission is restored. The kinetic stability of the strong blue emissive aggregate, Agg-2, can be regulated by the added concentration of the chemical fuel. Moreover, we expand the scope of this system within an agarose gel matrix, which allows us to gain spatiotemporal control over the properties, thereby producing a self-erasable writing system where the chemical fuel acts as the ink.
RESUMO
An intricate synergism between multiple biochemical processes and physical conditions determines the formation and function of various biological self-assemblies. Thus, a complex set of variables dictate the far-from-equilibrium nature of these biological assemblies. Mimicking such systems synthetically is a challenging task. We report multi-stimuli responsive transient coacervation of an aldehyde-appended polymer and a short peptide. The coacervates are formed by the disulphide linkages between the peptide molecules and the imine bond between the polymer and the peptide. Imines are susceptible to pH changes and the disulphide bonds can be tuned by oxidation/reduction processes. Thus, the coacervation is operational only under the combined effect of appropriate pH and oxidative conditions. Taking advantage of these facts, the coacervates are transiently formed under a pH cycle (urea-urease/gluconolactone) and a non-equilibrium redox cycle (TCEP/H2 O2 ). Importantly, the system showed high adaptability toward environmental changes. The transient existence of the coacervates can be generated without any apparent change in size and shape within the same system through the sequential application of the above-mentioned nonequilibrium reaction cycles. Additionally, the coacervation allows for efficient encapsulation/stabilisation of proteins. Thus, the system has the potential to be used for protein/drug delivery purposes in the future.
RESUMO
Here we report a highly efficient disulfide-driven peptide macrocyclization in 15 min on a solid support using persulfate as a crucial additive in iodine-mediated oxidative cyclization. The method eliminates the side products of classical iodine-mediated peptide cyclization. It is operationally simple and convenient for cyclizing small to lengthier peptides embodying popular cysteine building blocks in a single step.
Assuntos
Cisteína , Peptídeos , Peptídeos/química , Cisteína/química , Ciclização , Dissulfetos , Oxirredução , Peptídeos Cíclicos/químicaRESUMO
Life is fueled by multi-enzymatic tandem processes that display unmatched catalytic efficiencies owing to certain features of the biological reactors such as compartmentalization, nano-confinement, and out-of-equilibrium dynamics. With an attempt to match such natural catalytic systems, herein, we present a chemoenzymatic pH clock mediated transient assembly of a vesicular nanozyme. Distinct confinement of two catalytically discrete units, Histidine groups on the periphery and hemin in the lipid bilayer, results in an efficient hydrolase-peroxidase tandem catalysis in a temporally controlled fashion. The pH clock, constituted by alkaline TRIS (Tris(hydroxymethyl)aminomethane hydrochloride) buffer (promoter) and glucose oxidase (GOx) catalyzed oxidation of glucose, steers the transience in an asymmetric fashion. Alkaline TRIS buffer enhances the pH of the system and triggers the formation of imine linked Supramolecular Peptide Amphiphiles (SPAs) that further assemble into vesicles. On the other hand, oxidation of glucose produces gluconolactone and H2O2. Gluconolactone hydrolyzes to gluconic acid (deactivator) which dissipates the nanozyme while H2O2 is used in the peroxidase catalysis. Thus, the bi-directional feedback from the fuel not only regulates the existence of the transient state but also controls the activity of the assembly. The transiently assembled nanozyme protected the activity of the catalytic units, displayed substrate specificity and catalytic reproducibility over multiple fueling cycles.
Assuntos
Glucose Oxidase , Peróxido de Hidrogênio , Catálise , Retroalimentação , Glucose Oxidase/química , Compostos Macrocíclicos , Reprodutibilidade dos TestesRESUMO
A short peptide based hydrogel exhibits aqueous insolubility, thixotropy and efficient light induced syneresis. Upon irradiation with UV light, the hydrogel shrinks and expells â¼50% of the solvent. Syneresis is caused by light-triggered trans-cis isomerisation of an azobenzene moiety in the peptide derivative. This expulsion of solvent can be effectively exploited in the removal of low molecular weight contaminants in water.
Assuntos
Corantes/isolamento & purificação , Hidrogéis/química , Peptídeos/química , Poluentes Químicos da Água/isolamento & purificação , Compostos Azo/química , Compostos Azo/efeitos da radiação , Fracionamento Químico/métodos , Hidrogéis/efeitos da radiação , Peptídeos/efeitos da radiação , Solubilidade , Estereoisomerismo , Raios Ultravioleta , Água/químicaRESUMO
Unlike polymeric hydrogels, in the case of supramolecular hydrogels, the cross-linked network formation is governed by non-covalent forces. Hence, in these cases, the gelator molecules inside the network retain their characteristic physicochemical properties as no covalent modification is involved. Supramolecular hydrogels thus get dissolved easily in aqueous medium as the dissolution leads to a gain in entropy. Thus, any supramolecular hydrogel, insoluble in bulk water, is beyond the present understanding and hitherto not reported as well. Herein, we present a peptide-based (PyKC) hydrogel which remained insoluble in water for more than a year. Moreover, in the gel state, any movement of solvent or solute to and from the hydrogel is highly restricted resulting in a high degree of compartmentalization. The hydrogel could be re-dissolved in the presence of some biomolecules which makes it a prospective material for in vivo applications. Experimental studies and all atom molecular dynamics simulations revealed that a cysteine containing gelator forms dimers through disulfide linkage which self-assemble into PyKC layers with a distinct PyKC-water interface. The hydrogel is stabilized by intra-molecular hydrogen bonds within the peptide-conjugates and the π-π stacking of the pyrene rings. The unique confinement ability of the hydrogel is attributed to the slow dynamics of water which remains confined in the core region of PyKC via hydrogen bonds. The hydrogen bonds present in the confined water need activation energies to move through the water depleted hydrophobic environment of pyrene rings which significantly reduces water transport across the hydrogel. The compartmentalizing ability is effectively used to protect enzymes for a long time from denaturing agents like urea, heat or methanol. Overall, the presented system shows unique insolubility and confinement properties that could be a milestone in the research of soft-materials.
RESUMO
Cation-π and charge-transfer (CT) interactions are ubiquitous in nature and involved in several biological processes. Although the origin of both the interactions in isolated pairs has extensively been studied, CT interactions are more prominent in supramolecular chemistry. Involvement of cation-π interactions in the preparation of advanced functional soft materials is uncommon. Moreover, a combination of these two interactions within a pair of electron donor (D) and acceptor (A) is uncharted. Here, we present a rational design to incorporate a combination of these two interactions within a D-A pair. A pyrene-peptide conjugate exhibits a combination of cation-π and CT interactions with a cationic naphthalenediimide (NDI) molecule in water. Nuclear Overhauser effect spectroscopy NMR along with other techniques and density functional theory calculations reveal the involvement of these interactions. The π-planes of pyrene and NDI adopt an angle of 56° to satisfy both the interactions, whereas ß-sheet formation by the peptide sequence facilitates self-assembly. Notably, the binary system forms a self-supporting hydrogel at a higher concentration. The hydrogel shows efficient self-healing and injectable property. The hydrogel retains its thixotropic nature even at an elevated temperature. Broadly, we demonstrate a pathway that should prove pertinent to various areas, ranging from understanding biological assembly to peptide-based functional soft materials.
RESUMO
Charge transfer (CT) complexes between electron donor and acceptor molecules provide unique alternate D-A arrangements. However, these arrangements cannot be fully translated into chemo-selective organic transformations as the dynamicity of CT complexes in solution results in the co-existence of D-A assemblies and free monomers during the reaction time-scale. A conceptually new strategy to exploit CT complexes toward chemo-selective products by means of seizing the dynamicity of CT complexes is reported here. Aqueous CT complexes of donor and acceptor molecules bearing reactive thiol groups were frozen instantly and cryo-desiccated to get the alternate D-A assemblies intact in the solid state. Oxidation of reactive thiols in an oxygen rich solvent in the solid state resulted in the formation of the hetero-dimer exclusively. CT complexation and appropriate molecular arrangements are the key factors behind successful execution of this novel methodology. The strategy also paves the way to prepare unsymmetrical disulfide molecules from two dissimilar thiols.