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Now showing items 1 - 16 of 2307

  • α‐Helix‐Mimetic Foldamers for Targeting HIV‐1 TAR RNA

    Maity, Debabrata   Kumar, Sunil   Curreli, Francesca   Debnath, Asim K.   Hamilton, Andrew D.  

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  • alpha-Helix Mimetics as Modulators of A beta Self-Assembly

    Kumar, Sunil   Hamilton, Andrew D.  

    A key molecular species in Alzheimer's disease (AD) is the A beta(42) alloform of A beta peptide, which is dominant in the amyloid plaques deposited in the brains of AD patients. Recent studies have decisively demonstrated that the prefibrillar soluble oligomers are the neurotoxic culprits and are associated with the pathology of AD. Nascent A beta(42) is predominantly disordered but samples alpha-helical conformations covering residues 15-24 and 29-35 in the presence of micelles and structure-inducing solvents. In this report, a focused library of oligopyridylamide based alpha-helical mimetics was designed to target the central alpha-helix subdomain of A beta (A beta(13-26)). A tripyridylamide, ADH-41, was identified as one of the most potent antagonists of A beta fibrillation. Amyloid-assembly kinetics, transmission electron microscopy (TEM), and atomic force microscopy (AFM) show that ADH-41 wholly suppresses the aggregation of A beta at a substoichiometric dose. Dot blot and ELISA assays demonstrate the inhibition of the putative neurotoxic A beta oligomers. ADH-41 targets. A beta in a sequence and structure-specific manner, as it did not have any effect on the aggregation of islet amyloid polypeptide (IAPP), a peptide which shares sequence similarity with A beta. Spectroscopic studies using NMR and CD confirm induction of alpha-helicity in A beta mediated by ADH-41. Calorimetric and fluorescence titrations yielded binding affinity in the low micromolar range. ADH-41 was also effective at inhibiting the seed-catalyzed aggregation of A beta probably by modulating the A beta conformation into a fiber incompetent structure. Overall, we speculate that ADH-41 directs A beta into off-pathway structures, and thereby alters various solution based functions of A beta. Cell-based assays to assess the effect of ADH-41 on A beta are underway and will be presented in due course.
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  • Mimicry of a beta-Hairpin Turn by a Nonpeptidic Laterally Flexible Foldamer

    Meisel, Joseph W.   Hu, Chunhua T.   Hamilton, Andrew D.  

    The design and characterization of a proteomimetic foldamer that displays lateral flexibility endowed by intramolecular bifurcated hydrogen bonds is reported. The MAMBA scaffold, derived from meta-aminomethylbenzoic acid, adopts a serpentine conformation that mimics the side chain projection of all four residues in a beta-hairpin turn.
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  • Acid-mediated topological control in a functionalized foldamer

    Knipe, Peter C.   Thompson, Sam   Hamilton, Andrew D.  

    Induced conformational change provides a powerful mechanism to modulate the structure and function of molecules. Here we describe the synthesis of chiral, surface-functionalized oligomeric pyridine/imidazolidin-2-one foldamers, and interrogate their acid-mediated transition between linear and helical topologies.
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  • Heterofunctionalized Cavitands by Macrocyclization of Sequence-Defined Foldamers

    Meisel, Joseph W.   Hu, Chunhua T.   Hamilton, Andrew D.  

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  • Hybrid Diphenylalkyne-Dipeptide Oligomers Induce Multistrand -Sheet Formation

    Ross, Jonathan E.   Knipe, Peter C.   Thompson, Sam   Hamilton, Andrew D.  

    Functionalized diphenylalkynes provide a template for the presentation of protein-like surfaces composed of multistrand -sheets. The conformational properties of three-, four-, and seven-stranded systems have been investigated in the solid- and solution-state. This class of molecule may be suitable for the mediation of therapeutically relevant protein-protein interactions.
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  • Design and Synthesis of Oligoamide-Based Double -Helix Mimetics

    Kulikov, Oleg V.   Thompson, Sam   Xu, Hai   Incarvito, Christopher D.   Scott, Richard T. W.   Saraogi, Ishu   Nevola, Laura   Hamilton, Andrew D.  

    An extensive series of bis-oligobenzamides and bis-oligopyridylamides have been efficiently prepared and studied by X-ray analysis and computational methods. A modular synthesis led to double -helix mimics bearing between two and ten branched side-chains. The inter-helix angle and distance can be tuned by varying the length and rigidity of the spacer, thereby reproducing the recognition domains of a range of super-secondary structures.
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  • Enaminone-Based Mimics of Extended and Hydrophilic alpha-Helices

    Adler, Marc J.   Scott, Richard T. W.   Hamilton, Andrew D.  

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  • Aryl-linked imidazolidin-2-ones as non-peptidic beta-strand mimetics

    Sutherell, Charlotte L.   Thompson, Sam   Scott, Richard T. W.   Hamilton, Andrew D.  

    We describe the design and synthesis of a non-peptidic beta-strand mimetic composed of alternating aryl and imidazolidin-2-one rings that can be adapted to display diverse side-chains. Solid-and solution-phase data together with calculations suggest that the desired conformation for side-chain mimicry is readily accessible and well-populated.
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  • A 1,3-phenyl-linked hydantoin oligomer scaffold as a beta-strand mimetic

    Jamieson, Andrew G.   Russell, David   Hamilton, Andrew D.  

    A synthetic scaffold that mimics a peptide beta-strand has been designed and synthesised based on a 1,3-phenyl-linked hydantoin oligomer. The conformational preferences of this oligomer were investigated using molecular modelling and solution NMR experiments and suggest a planar conformation that accurately mimics the i, i + 2 and i + 4 residues of a peptide beta-strand.
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  • pH-Dependent Conformational Switching in 2,6-Benzamidodiphenylacetylenes

    Jones, Ian M.   Lingard, Hannah   Hamilton, Andrew D.  

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  • Synthetic mimetics of protein secondary structure domains

    Ross, Nathan T.   Katt, William P.   Hamilton, Andrew D.  

    Proteins modulate the majority of all biological functions and are primarily composed of highly organized secondary structural elements such as helices, turns and sheets. Many of these functions are affected by a small number of key protein-protein contacts, often involving one or more of these well-defined structural elements. Given the ubiquitous nature of these protein recognition domains, their mimicry by peptidic and non-peptidic scaffolds has become a major focus of contemporary research. This review examines several key advances in secondary structure mimicry over the past several years, particularly focusing upon scaffolds that show not only promising projection of functional groups, but also a proven effect in biological systems.
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  • A Modular Synthesis of Conformationally Preorganised Extended beta-Strand Peptidomimetics

    Yamashita, Tohru   Knipe, Peter C.   Busschaert, Nathalie   Thompson, Sam   Hamilton, Andrew D.  

    A promising strategy for mediating protein-protein interactions is the use of non-peptidic mimics of secondary structural protein elements, such as the a-helix. Recent work has expanded the scope of this approach by providing proof-of-principle scaffolds that are conformationally biased to mimic the projection of side-chains from one face of another common secondary structural element-the beta-strand. Herein, we present a synthetic route that has key advantages over previous work: monomers bearing an amino acid side-chain were pre-formed before rapid assembly to peptidomimetics through a modular, iterative strategy. The resultant oligomers of alternating pyridyl and six-membered cyclic ureas accurately reproduce a recognition domain of several amino acid residues of a beta-strand, demonstrated herein by mimicry of the i, i + 2, i + 4 and i + 6 residues.
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  • Design and Evaluation of Nonfluorous CO(2)-Soluble Oligomers and Polymers

    Wang, Yang   Hong, Lei   Tapriyal, Deepak   Kim, In Chul   Paik, Ik-Hyeon   Crosthwaite, Jacob M.   Hamilton, Andrew D.   Thies, Mark C.   Beckman, Eric J.   Enick, Robert M.   Johnson, J. Karl  

    Ab initio molecular modeling is used to design nonfluorous polymers that are potentially soluble in liquid CO(2). We have used calculations to design three nonfluorous compounds meant to model the monomeric repeat units of polymers that exhibit multiple favorable binding sites for CO(2). These compounds are methoxy isopropyl acetate, 2-methoxy ethoxy-propane, and 2-methoxy methoxy-propane. We have synthesized oligomers or polymers based on these small compounds and have tested their solubility in CO,). All three of these exhibit appreciable solubility ill CO(2). At 25 degrees C, oligo(3-acetoxy oxetane)6 is 5 wt % soluble at 25 MPa, the random copolymer (vinyl methoxymethyl ether(30)-co-vinyl acetate(9)) is 5 wt % soluble at 70 MPa and random copolymer (vinyl 1-methoxyethyl ether(30)-co-vinyl acetate(9)) is 3 wt % soluble at 120 MPa. These oligomers and polymers represent new additions to the very short list of nonfluorous CO(2)-soluble polymers. However, none of these are more soluble than poly(vinyl acetate), which exhibits the highest CO(2) solubility of any known polymer containing only the elements C, H, and O.
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  • Combinatorial protein recognition as an alternative approach to antibody-mimetics

    Margulies, David   Hamilton, Andrew D.  

    Current approaches to medical diagnostics and drug design are largely based on the ability of monoclonal antibodies or synthetic molecules to bind proteins with high affinity and selectivity. In recent years, however, an alternative approach to protein recognition has emerged, in which proteins are identified using non-specific receptor arrays that are inspired by the olfactory neural system. An ultimate challenge for such systems is realizing a single, high-throughput analytical device that can effectively diagnose a range of medicinally relevant proteins. Such devices might overcome the difficulties associated with designing potent synthetic receptors for proteins and hence, could open up new possibilities in medical diagnostics, pathogen detection, and proteomics. Here we summarize recent developments in this area and also highlight its limitations and the challenges that this exciting interdisciplinary field faces. In particular, the goal of this review is to underscore the basic parameters required for obtaining combinatorial sensors for proteins and more importantly, to elucidate the rational methodologies that can be applied for systematically improving these promising analytical devices.
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  • Foldamer-Mediated Structural Rearrangement Attenuates A beta Oligomerization and Cytotoxicity

    Kumar, Sunil   Henning-Knechtel, Anja   Chehade, Ibrahim   Magzoub, Mazin   Hamilton, Andrew D.  

    The conversion of the native random coil amyloid beta (A beta) into amyloid fibers is thought to be a key event in the progression of Alzheimer's disease (AD). A significant body of evidence suggests that the highly dynamic A beta oligomers are the main causal agent associated with the onset of AD. Among many potential therapeutic approaches, one is the Modulation of A beta conformation into off-pathway structures to avoid the formation of the putative neurotoxic A beta oligomers. A library of oligoquinolines was screened to identify antagonists of A beta oligomerization, amyloid formation, and cytotoxicity. A dianionic tetraquinoline, denoted as 5, was one of the most potent antagonists of A beta fibrillation. Biophysical assays including amyloid kinetics, dot blot, ELISA, and TEM show that 5 effectively inhibits both A beta oligomerization and fibrillation. The antagonist activity of 5 toward A beta aggregation diminishes with sequence and positional changes in the surface functionalities. 5 binds to the central discordant alpha-helical region and induces a unique a-helical conformation in A beta. Interestingly, 5 adjusts its conformation to optimize the antagonist activity against A beta. 5 effectively rescues neuroblastoma cells from A beta-mediated cytotoxicity and antagonizes fibrillation and cytotoxicity pathways of secondary nucleation induced by seeding. 5 is also equally effective in inhibiting preformed oligomer-mediated processes. Collectively, 5 induces strong secondary structure in A beta and inhibits its functions including oligomerization, fibrillation, and cytotoxicity.
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