Supramolecular chemical biology: designed receptors and dynamic chemical systems.

Supramolecular chemistry focuses on the study of species joined by non-covalent interactions, and therefore on dynamic and relatively ill-defined structures. Despite being a well-developed field, it has to face important challenges when dealing with the selective recognition of biomolecules in highly competitive biomimetic media. However, supramolecular interactions reside at the core of chemical biology systems, since many processes in nature are governed by weak, non-covalent, strongly dynamic contacts.

Discovery of selective monosaccharide receptors dynamic combinatorial chemistry.

The molecular recognition of saccharides by synthetic hosts has become an appealing but elusive task in the last decades. Herein, we combine Dynamic Combinatorial Chemistry (DCC) for the rapid self-assembly and screening of virtual libraries of receptors, with the use of ITC and NMR to validate the hits and molecular modelling to understand the binding mechanisms. We discovered a minimalistic receptor, 1F (-benzyl-L-phenylalanine), with considerable affinity for fructose ( = 1762 M) and remarkable selectivity (>50-fold) over other common monosaccharides.

Molecular Recognition of Tyrosine-Containing Polypeptides with Pseudopeptidic Cages Unraveled by Fluorescence and NMR Spectroscopies.

The molecular recognition of Tyr-containing peptide copolymers with pseudopeptidic cages has been studied using a combination of fluorescence and NMR spectroscopies. Fluorescence titrations rendered a reasonable estimation of the affinities, despite the presence of dynamic quenching masking the unambiguous detection of the supramolecular complexes. Regarding NMR, the effect of polypeptide (PP) binding on relaxation and diffusion parameters of the cages is much more reliable than the corresponding chemical shift perturbations.

Pseudopeptidic host adaptation in peptide recognition unveiled by ion mobility mass spectrometry.

Complexation of the glutamic-tyrosine-glutamic tripeptide (EYE) with a series of pseudopeptidic cages has been thoroughly investigated using different analytical techniques. The stoichiometry and affinities of the supramolecular host : guest complexes both in aqueous solution and in the gas-phase were obtained from a suitable combination of fluorescence spectroscopy, NMR, and mass spectrometry (MS) methods. The cages bearing basic groups (lysine, ornitine and histidine) display the tightest EYE binding in aqueous media following the order CyHis > CyLys > CyOrn, thus suggesting that Tyr side chain encapsulation is additionally modulated by the identity of the cage side chains and their ability to be engaged in polar interactions with the EYE peptide.

A Degenerate Metal-Templated Catalytic System with Redundant Functional Groups for the Asymmetric Aldol Reaction.

A degenerate zinc-templated catalytic system containing two bipyridine ligands with redundant functional groups for either enamine or hydrogen bond formation was applied to the asymmetric aldol reaction. This concept led to both a higher probability of reaction and rate acceleration. Thus, the catalyst loading could be decreased to a remarkable 2 mol % in what we think is a general approach.

Inhibition of Sema-3A Promotes Cell Migration, Axonal Growth, and Retinal Ganglion Cell Survival.

Purpose: Semaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic approach for neuroprotection via inhibition of the Sema-3A pathway.

Molecular cages for biological applications.

Artificial receptors able to recognise biologically relevant molecules or ions have gained interest in the chemical community because they offer a plethora of posibilities. Molecular cage compounds are polycyclic compounds with a cavity designed for the encapsulation of guest species. Once inside the host cavity, the substrate can be transported through membranes and protected from the action of enzymes or other reactive species, thus offering the possibility of interfering with biological systems.

Semaphorin 3A-Glycosaminoglycans Interaction as Therapeutic Target for Axonal Regeneration.

Semaphorin 3A (Sema3A) is a cell-secreted protein that participates in the axonal guidance pathways. Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal growth and propagation. Therefore, interfering with Sema3A signaling is proposed as a therapeutic target for achieving functional recovery after CNS injuries.

Modulation of Src Kinase Activity by Selective Substrate Recognition with Pseudopeptidic Cages.

The selective recognition of tyrosine residues in peptides is an appealing approach to inhibiting their tyrosine kinase (TK)-mediated phosphorylation. Herein, we describe pseudopeptidic cages that efficiently protect substrates from the action of the Src TK enzyme, precluding the corresponding Tyr phosphorylation. Fluorescence emission titrations show that the most efficient cage inhibitors strongly bind the peptide substrates with a very good correlation between the binding constant and the inhibitory potency.

Spontaneous macrocyclization through multiple dynamic cyclic aminal formation.

The use of aminals in dynamic covalent chemistry is slightly underexplored, probably due to their inherent instability. Here we report the spontaneous [2+2] macrocyclization of tetrakis(aminals). Their unexpected stability and structural modularity, the dynamic nature of the connections and their water tolerance make them appealing systems for future applications as stimulus-responsive materials.

Dynamic Stereoselection of Peptide Helicates and Their Selective Labeling of DNA Replication Foci in Cells*.

Although largely overlooked in peptide engineering, coordination chemistry offers a new set of interactions that opens unexplored design opportunities for developing complex molecular structures. In this context, we report new artificial peptide ligands that fold into chiral helicates in the presence of labile metal ions such as Fe and Co . Heterochiral β-turn-promoting sequences encode the stereoselective folding of the peptide ligands and define the physicochemical properties of their corresponding metal complexes.

Exploiting complexity to implement function in chemical systems.

Chemistry deals with complex molecular systems that can be further connected by supramolecular interactions and reaction networks. However, chemists have taken little advantage of the intrinsic complexity of chemical systems, probably due to the lack of appropriate tools to analyse and understand complexity. In the last few decades, the concept of complexity has grown appealing: it allows the design of networks and dynamic systems expressing emerging properties and functions, which would be difficult to achieve from the mere addition of the components of the ensemble.

MCR-ALS analysis of H NMR spectra by segments to study the zebrafish exposure to acrylamide.

Metabolomics is currently an important field within bioanalytical science and NMR has become a key technique for drawing the full metabolic picture. However, the analysis of H NMR spectra of metabolomics samples is often very challenging, as resonances usually overlap in crowded regions, hindering the steps of metabolite profiling and resonance integration. In this context, a pre-processing method for the analysis of 1D H NMR data from metabolomics samples is proposed, consisting of the blind resolution and integration of all resonances of the spectral dataset by multivariate curve resolution-alternating least squares (MCR-ALS).

Live-Cell-Templated Dynamic Combinatorial Chemistry.

Dynamic covalent chemistry combines in a single step the screening and synthesis of ligands for biomolecular recognition. In order to do that, a chemical entity is used as template within a dynamic combinatorial library of interconverting species, so that the stronger binders are amplified due to the efficient interaction with the target. Here we employed whole A549 living cells as template in a dynamic mixture of imines, for which amplification reflects the efficient and selective interaction with the corresponding extracellular matrix.

Molecular Recognition of Zwitterions with Artificial Receptors.

Many biomolecules exist as internal ion pairs or zwitterions within a biologically relevant pH range. Despite their importance, the molecular recognition of this type of systems is specially challenging due to their strong solvation in aqueous media, and their trend to form folded or self-assembled structures by pairing of charges of different sign. In this Minireview, we will discuss the molecular recognition of zwitterions using non-natural, synthetic receptors.

Targeting redox metabolism: the perfect storm induced by acrylamide poisoning in the brain.

Exposure to acrylamide may lead to different neurotoxic effects in humans and in experimental animals. To gain insights into this poorly understood type of neurotoxicological damage, we used a multi-omic approach to characterize the molecular changes occurring in the zebrafish brain exposed to acrylamide at metabolite, transcript and protein levels. We detected the formation of acrylamide adducts with thiol groups from both metabolites and protein residues, leading to a quasi-complete depletion of glutathione and to the inactivation of different components of the thioredoxin system.

Synthesis of second-generation self-assembling Gemini Amphiphilic Pseudopeptides.

Hypothesis: The structural modularity of Gemini Amphiphilic Pseudopeptides (GAPs) allows the tuning of the self-assembling properties by slight modifications in the chemical structures. We hypothesized that the introduction of a flexible linker containing a central nitrogen atom in bipodal and tripodal GAPs would improve their self-assembly properties in aqueous media.

Experiments: After preparation of the corresponding GAPs, a combination of SEM, TEM and AFM techniques were used to study the morphology of the self-assembled structures in different media.

pH-Dependent Chloride Transport by Pseudopeptidic Cages for the Selective Killing of Cancer Cells in Acidic Microenvironments.

Acidic microenvironments in solid tumors are a hallmark of cancer. Inspired by that, we designed a family of pseudopeptidic cage-like anionophores displaying pH-dependent activity. When protonated, they efficiently bind chloride anions.

An efficient dynamic asymmetric catalytic system within a zinc-templated network.

Enhanced cooperativity leading to high catalytic activity and stereoselectivity has been achieved through a complex network of simple species interacting reversibly. This novel dynamic catalytic system relies on bipyridine-based organocatalytic ligands and zinc(ii) as the template. It demonstrates the effectiveness of dealing with mixtures rather than single species in asymmetric catalysis.

Comparative analysis of H NMR and H-C HSQC NMR metabolomics to understand the effects of medium composition in yeast growth.

In nuclear magnetic resonance (NMR) metabolomics, most of the studies have been focused on the analysis of one-dimensional proton (1D H) NMR, whereas the analysis of other nuclei, such as C, or other NMR experiments are still underrepresented. The preference of 1D H NMR metabolomics lies on the fact that it has good sensitivity and a short acquisition time, but it lacks spectral resolution because it presents a high degree of overlap. In this study, the growth metabolism of yeast ( Saccharomyces cerevisiae) was analyzed by 1D H NMR and by two-dimensional (2D) H-C heteronuclear single quantum coherence (HSQC) NMR spectroscopy, leading to the detection of more than 50 metabolites with both analytical approaches.

Dynamic Covalent Identification of an Efficient Heparin Ligand.

Despite heparin being the most widely used macromolecular drug, the design of small-molecule ligands to modulate its effects has been hampered by the structural properties of this polyanionic polysaccharide. Now a dynamic covalent selection approach is used to identify a new ligand for heparin, assembled from extremely simple building blocks. The amplified molecule strongly binds to heparin (K in the low μm range, ITC) by a combination of electrostatic, hydrogen bonding, and CH-π interactions as shown by NMR and molecular modeling.

Deciphering the Underlying Metabolomic and Lipidomic Patterns Linked to Thermal Acclimation in Saccharomyces cerevisiae.

Temperature is one of the most critical parameters for yeast growth, and it has deep consequences in many industrial processes where yeast is involved. Nevertheless, the metabolic changes required to accommodate yeast cells at high or low temperatures are still poorly understood. In this work, the ultimate responses of these induced transcriptomic effects have been examined using metabolomics-derived strategies.

A Dynamic Chemical Network for Cystinuria Diagnosis.

The study of molecular networks represents a conceptual revolution in chemistry. Building on previous knowledge and after understanding the rules of non-covalent interactions, the design of stimulus-responsive chemical systems is possible. Herein we report a new strategy, based on the reorganization of a dynamic chemical network that generates new fluorescent associations in the presence of cysteine or cystine.

Sensing, Transport and Other Potential Biomedical Applications of Pseudopeptides.

Pseudopeptides are privileged synthetic molecules built from the designed combination of peptide-like and abiotic artificial moieties. Consequently, they are benefited from the advantages of both families of chemical structures: modular synthesis, chemical and functional diversity, tailored three-dimensional structure, usually high stability in biological media and low non-specific toxicity. Accordingly, in the last years, these compounds have been used for different biomedical applications, ranging from bio-sensing, ion transport, the molecular recognition of biologically relevant species, drug delivery or gene transfection.