Peptide and Enzyme Catalysts Work in Concert in Stereoselective Cascade Reactions-Oxidation followed by Conjugate Addition.

Enzymes and peptide catalysts consist of the same building blocks but require vastly different environments to operate best. Herein, we show that an enzyme and a peptide catalyst can work together in a single reaction vessel to catalyze a two-step cascade reaction with high chemo- and stereoselectivity. Abundant linear alcohols, nitroolefins, an alcohol oxidase, and a tripeptide catalyst provided chiral γ-nitroaldehydes in aqueous buffer. High yields (up to 92 %) and stereoselectivities (up to 98 % ee) were achieved for the cascade through the rational design of the peptide catalyst and the identification of common reaction conditions.

Modifying the Catalytic Activity of Lipopeptide Assemblies with Nucleobases.

Biohybrid catalysts that operate in aqueous media are intriguing for systems chemistry. In this paper, we investigate whether control over the self-assembly of biohybrid catalysts can tune their properties. As a model, we use the catalytic activity of functional hybrid molecules consisting of a catalytic H-dPro-Pro-Glu tripeptide, derivatized with fatty acid and nucleobase moieties. This combination of simple biological components merged the catalytic properties of the peptide with the self-assembly of the lipid, and the structural ordering of the nucleobases. The biomolecule hybrids self-assemble in aqueous media into fibrillar assemblies and catalyze the reaction between butanal and nitrostyrene. The interactions between the nucleobases enhanced the order of the supramolecular structures and affected their catalytic activity and stereoselectivity. The results point to the significant control and ordering that nucleobases can provide in the self-assembly of biologically inspired supramolecular catalysts.

Amine Catalysis with Substrates Bearing N-Heterocyclic Moieties Enabled by Control over the Enamine Pyramidalization Direction.

Stereoselective organocatalytic C-C bond formations that tolerate N-heterocycles are valuable since these moieties are common motifs in numerous chiral bioactive compounds. Such transformations are, however, challenging since N-heterocyclic moieties can interfere with the catalytic reaction. Here, we present a peptide that catalyzes conjugate addition reactions between aldehydes and nitroolefins bearing a broad range of different N-heterocyclic moieties with basic and/or H-bonding sites in excellent yields and stereoselectivities. Tuning of the pyramidalization direction of the enamine intermediate enabled the high stereoselectivity.

Effect of the enamine pyramidalization direction on the reactivity of secondary amine organocatalysts.

Chiral secondary amines are valuable catalysts for reactions that proceed through an enamine intermediate. Here, we explored the importance of the pyramidalization direction of the enamine-N on the reactivity of chiral enamines with a combination of computational, NMR spectroscopic, and kinetic experiments. Studies with peptidic catalysts that bear cyclic amines with different ring sizes revealed that endo-pyramidalized enamines are significantly more reactive compared to exo-pyramidalized analogs. The results show that the pyramidalization direction can have a greater effect than n→π* orbital overlap on the reactivity of chiral enamines. The data enabled the development of a catalyst with higher reactivity compared to the parent catalyst.

Proximity-Induced Bioorthogonal Chemistry Using Inverse Electron Demand Diels-Alder Reaction.

Bioorthogonal chemistry techniques enable the selective and targeted manipulation of living systems. In order to yield universally applicable techniques, it is of great importance for bioorthogonal reactions to take place rapidly, selectively, and with the formation of only benign side products. One of the reactions that match these criteria well is the inverse electron demand Diels-Alder reaction (DAinv) between tetrazines and strained dienophiles. However, even this prime technique comes with the disadvantage of its reactants having limited stability under physiological conditions. In our protocol, an unreactive and therefore stable DAinv diene/dienophile pair reacts rapidly using DNA hybridization as secondary rate-accelerating process. Due to the fluorogenicity of the presented tetrazine rhodamine conjugate, this method enables the selective screening and evaluation of reactant pairs for proximity-mediated bioorthogonal chemistry.

Silver bullets: A new lustre on an old antimicrobial agent.

Silver was widely used in medicine to treat bacterial infections in the 19th and early 20th century, up until the discovery and development of the first modern antibiotics in the 1940s, which were markedly more effective. Since then, every new antibiotic introduced to the clinic has led to an associated development of drug resistance. Today, the threat of extensive bacterial resistance to antibiotics has reignited interest in alternative strategies to treat infectious diseases, with silver regaining well-deserved renewed attention. Silver ions are highly disruptive to bacterial integrity and biochemical function, with comparatively minimal toxicity to mammalian cells. This review focuses on the antimicrobial properties of silver and their use in synergistic combination therapy with traditional antibiotic drugs.

A Bifunctional Fluorogenic Rhodamine Probe for Proximity-Induced Bioorthogonal Chemistry.

Bioorthogonal reactions have emerged as a versatile tool in life sciences. The inverse electron demand Diels-Alder reaction (DAinv ) stands out due to the availability of reactants with very fast kinetics. However, highly reactive dienophiles suffer the disadvantage of being less stable and prone to side reactions. Herein, we evaluate the extent of acceleration of rather unreactive but highly stable dienophiles by DNA-templated proximity. To this end, we developed a modular synthetic route for a novel bifunctional fluorogenic tetrazine rhodamine probe that we used to determine the reaction kinetics of various dienophiles in a fluorescence assay. Under proximity-driven conditions the reaction was found to be several orders of magnitude faster, and we observed almost no background reaction when proximity was not induced. This fundamental study identifies a minimally sized fluorogenic tetrazine dienophile reactant pair that has potential to be generally used for the visualization of biomolecular interactions with temporal and spatial resolution in living systems.

Enhancement of antibiotic-activity through complexation with metal ions - Combined ITC, NMR, enzymatic and biological studies.

Alternative solutions need to be developed to overcome the growing problem of multi-drug resistant bacteria. This study explored the possibility of creating complexes of antibiotics with metal ions, thereby increasing their activity. Analytical techniques such as isothermal titration calorimetry and nuclear magnetic resonance were used to examine the structure and interactions between Cu(II), Ag(I) or Zn(II) and ß-lactam antibiotics. The metal-ß-lactam complexes were also tested for antimicrobial activity, by micro-broth dilution and disk diffusion methods, showing a synergistic increase in the activity of the drugs, and enzymatic inhibition assays confirming inhibition of ß-lactamases responsible for resistance. The metal-antibiotic complex concept was proven to be successful with the activity of the drugs enhanced against ß-lactamase-producing bacteria. The highest synergistic effects were observed for complexes formed with Ag(I).