The hairpin ribozyme catalyzes sequence-specific cleavage of RNA through transesterification of the scissile phosphate. Vanadate has previously been used as a transition state mimic of protein enzymes that catalyze the same reaction. Comparison of the 2.2 angstrom resolution structure of a vanadate-hairpin ribozyme complex with structures of precursor and product complexes reveals a rigid active site that makes more hydrogen bonds to the transition state than to the precursor or product. Because of the paucity of RNA functional groups capable of general acid-base or electrostatic catalysis, transition state stabilization is likely to be an important catalytic strategy for ribozymes.

Nature provides many examples of soft gel-like materials where performance is determined by tuning time-dependent mechanical properties with dynamic bonding interactions between biomacromolecules.[1] Accordingly, synthetic gels that contain dynamic bonding interactions have undergone intense investigation in fundamental and applied material science. The balance of solid-like and fluid-like behavior in these gel networks results from the binding equilibrium of reversible crosslinks between polymer chains. [2][3][4][5] Contemporary research on gels has focused on self-assembled systems [6][7][8][9][10][11][12][13][14][15] usually exploiting hydrogen bonding interactions. However, gels crosslinked with reversible covalent bonding chemistries [16][17][18] would provide an energetically favorable, [19] specific and controlled mechanism for engineering functional dynamic networks. [20][21][22][23][24] We have synthesized hydrogel networks that form in the physiological pH range by the reversible covalent interaction of polymer-bound phenylboronic acid and salicylhydroxamic acid (Fig. 1). These gels demonstrate a spectrum of pH-dependent viscoelastic behavior that can be controlled by the chemical composition of the polymer backbone. Moreover, the reversible crosslinks allow these networks to restructure dynamically and self-heal after mechanical disruption. Phenylboronate-salicylhydroxamate gels provide a new class of self-assembled materials enabling precise control over network viscoelasticity and pH responsiveness. Water-soluble polymers containing 10 mol % phenylboronic acid (PBA) or 10 mol % salicylhydroxamic acid (SHA) were synthesized by free-radical polymerization of functionalized monomers with 2-hydroxypropylmethacrylamide (HPMA) or acrylic acid (AA; Fig. 1b). When aqueous solutions of PBA and SHA containing polymers are mixed at physiological pH, the PBA and SHA moieties associate to form coordinate covalent bonds [25][26][27] (PBA-SHA; Fig. 1a). c Figure 1. Self-healing, viscoelastic hydrogel networks are formed using reversible covalent crosslinking chemistry. a) Covalent bonds that form between polymer-bound phenylboronic acid (PBA) and salicylhydroxamic acid (SHA) have pH-dependent binding equilibria that are shifted to the uncrosslinked state under acidic conditions. b) Linear water-soluble polymers containing either PBA or SHA moieties can be easily synthesized with different polymer backbones (e.g., 2-hydroxypropylmethacrylamide (HPMA) or acrylic acid (AA)) of controlled molar feed ratios. Two degrees of substitution for each polymer were made with x = 90 mol % or 95 mol % (see Supporting Information Table S1 for details). c) When PBA-and SHA-containing polymer solutions are mixed under physiological conditions, a reversible semisolid gel forms due to the dynamic restructuring of the crosslinked gel network. The specific pH range at which gels behave reversibly can be controlled with choice of polymer backbone (in b); HPMA-based PBA-SHA crosslinked gels are reversible at mildly acidic pH (pH 4-5) whi...

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The development of targeted vehicles for systemic drug delivery relies on optimizing both the cell-targeting ligand and the physicochemical characteristics of the nanoparticle carrier. A versatile platform based on modification of gold nanoparticles with thiolated polymers is presented in which design parameters can be varied independently and systematically. Nanoparticle formulations of varying particle size, surface charge, surface hydrophilicity, and galactose ligand density were prepared by conjugation of PEG-thiol and galactose-PEG-thiol to gold colloids. This platform was applied to screen for nanoparticle formulations that demonstrate hepatocyte-targeted delivery in vivo. Nanoparticle size and the presence of galactose ligands were found to significantly impact the targeting efficiency. Thus, this platform can be readily applied to determine design parameters for targeted drug delivery systems.Modified gold nanoparticles are a suitable model for nanoparticle-based gene carriers.

Cover: The picture depicts a versatile, goldbased platform developed to optimize nanoparticle properties. Nanoparticles with optimal size, hydrophilicity and ligand display successfully target hepatocytes. The design properties determined by this method can be applied to develop targeted nanoparticulate drug carriers. Further details can be found in the article by J. M. Bergen, H.