The Experts below are selected from a list of 3351 Experts worldwide ranked by ideXlab platform

Bruce E. Maryanoff - One of the best experts on this subject based on the ideXlab platform.

  • in vivo efficacy of hdl like nanolipid particles containing multivalent Peptide Mimetics of apolipoprotein a i
    Journal of Lipid Research, 2014
    Co-Authors: Yannan Zhao, Bruce E. Maryanoff, Audrey S Black, David J Bonnet, Linda K Curtiss, Luke J Leman, Reza M Ghadiri
    Abstract:

    We have observed that molecular constructs based on multiple apoA-I mimetic Peptides attached to a branched scaffold display promising anti-atherosclerosis functions in vitro. Building on these promising results, we now describe chronic in vivo studies to assess anti-atherosclerotic efficacy of HDL-like nanoparticles assembled from a trimeric construct, administered over 10 weeks either ip or orally to LDL receptor-null mice. When dosed ip, the trimer-based nanolipids markedly reduced plasma LDL-cholesterol levels by 40%, unlike many other apoA-I mimetic Peptides, and were substantially atheroprotective. Surprisingly, these nanoparticles were also effective when administered orally at a dose of 75 mg/kg, despite the Peptide construct being composed of l-amino acids and being undetectable in the plasma. The orally administered nanoparticles reduced whole aorta lesion areas by 55% and aortic sinus lesion volumes by 71%. Reductions in plasma cholesterol were due to the loss of non-HDL lipoproteins, while plasma HDL-cholesterol levels were increased. At a 10-fold lower oral dose, the nanoparticles were marginally effective in reducing atherosclerotic lesions. Intriguingly, analogous results were obtained with nanolipids of the corresponding monomeric Peptide. These nanolipid formulations provide an avenue for developing orally efficacious therapeutic agents to manage atherosclerosis.

  • High-affinity thrombin receptor (PAR-1) ligands: a new generation of indole-based Peptide mimetic antagonists with a basic amine at the C-terminus.
    Bioorganic & medicinal chemistry letters, 2003
    Co-Authors: Han-cheng Zhang, David F. Mccomsey, Kimberly White, Michael F. Addo, Patricia Andrade-gordon, Claudia K. Derian, Donna Oksenberg, Bruce E. Maryanoff
    Abstract:

    Abstract A new generation of indole-based Peptide Mimetics, bearing a basic amine at the C-terminus, was developed by the agency of two complementary, multistep, trityl resin-based approaches. Thus, we obtained several high-affinity thrombin receptor (PAR-1) ligands, such as 32 and 34. Compounds 32 and 34 were found to bind to PAR-1 with excellent affinity (IC50=25 and 35 nM, respectively) and to effectively block platelet aggregation induced by SFLLRN-NH2 (TRAP-6) and α-thrombin.

  • Thrombin receptor (PAR-1) antagonists. Solid-phase synthesis of indole-based Peptide Mimetics by anchoring to a secondary amide.
    Bioorganic & medicinal chemistry letters, 2001
    Co-Authors: Han-cheng Zhang, David F. Mccomsey, Kimberly White, Michael F. Addo, Patricia Andrade-gordon, Claudia K. Derian, Donna Oksenberg, Bruce E. Maryanoff
    Abstract:

    A novel, 10-step, solid-phase method, based on a secondary amide linker, was developed to construct a diverse library of indole-based SFLLR Peptide Mimetics as thrombin receptor (protease-activated receptor 1, PAR-1) antagonists. The key steps include stepwise reductive alkylation, urea formation, and Mannich reaction. Screening of the library led to a quick development of the SAR and the significant improvement of PAR-1 activity.

Karen Rowan - One of the best experts on this subject based on the ideXlab platform.

  • carbacyclic Peptide Mimetics as vcam vla 4 antagonists
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Jefferson Wright Tilley, Gerry Kaplan, Nader Fotouhi, Barry A Wolitzky, Karen Rowan
    Abstract:

    Abstract Substitution of carbon for sulfur in a potent 13-membered cyclic disulfide containing Peptide was accomplished via an intramolecular Wittig reaction and resulted in a series of ‘carba’ analogues. Potency in the VCAM–VLA-4 assay was sensitive to ring size and lower than that of the parent disulfide.

  • cyclic thioether Peptide Mimetics as vcam vla 4 antagonists
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Nader Fotouhi, Jefferson Wright Tilley, Karen Rowan, Pramod V Joshi, Virginia Schwinge, Barry A Wolitzky
    Abstract:

    Selective substitution of a sulfur atom by carbon in a highly potent 13-membered cyclic disulfide was accomplished by intramolecular displacement of a bromide. The potency of the resulting thioethers in the VCAM/VLA-4 assay was dependant on ring size and the position of the sulfur atom.

Barry A Wolitzky - One of the best experts on this subject based on the ideXlab platform.

  • carbacyclic Peptide Mimetics as vcam vla 4 antagonists
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Jefferson Wright Tilley, Gerry Kaplan, Nader Fotouhi, Barry A Wolitzky, Karen Rowan
    Abstract:

    Abstract Substitution of carbon for sulfur in a potent 13-membered cyclic disulfide containing Peptide was accomplished via an intramolecular Wittig reaction and resulted in a series of ‘carba’ analogues. Potency in the VCAM–VLA-4 assay was sensitive to ring size and lower than that of the parent disulfide.

  • cyclic thioether Peptide Mimetics as vcam vla 4 antagonists
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Nader Fotouhi, Jefferson Wright Tilley, Karen Rowan, Pramod V Joshi, Virginia Schwinge, Barry A Wolitzky
    Abstract:

    Selective substitution of a sulfur atom by carbon in a highly potent 13-membered cyclic disulfide was accomplished by intramolecular displacement of a bromide. The potency of the resulting thioethers in the VCAM/VLA-4 assay was dependant on ring size and the position of the sulfur atom.

Gabriele Varani - One of the best experts on this subject based on the ideXlab platform.

  • a small cyclic β hairpin Peptide mimics the rbfox2 rna recognition motif and binds to the precursor mirna 20b
    ChemBioChem, 2019
    Co-Authors: Matthew D Shortridge, Gabriele Varani
    Abstract:

    : The RNA recognition motif (RRM), which is the most abundant RNA-binding motif in eukaryotes, is a well-structured domain of about 90 amino acids, yet the β2β3 hairpin, corresponding to strands 2 and 3 of the β-sheet, and the intervening loop make essential interactions with RNA in many RRM complexes. A series of small cyclic Peptide mimics of the β2β3 hairpin of Rbfox2 protein that recognize the terminal loop of precursor miR-20b have been designed to investigate whether the full RNA-binding protein can be mimicked with a minimal structurally preorganized Peptide. Within a small library of seven cyclic Peptides, a Peptide with low-micromolar affinity for the miR-20b precursor was found. NMR spectroscopy titration data suggest that this Peptide specifically targets the apical loop of pre-miR-20b. This work shows that it is possible to mimic RNA-binding proteins with designed stable Peptides, which provide a starting point for designing or evolving small Peptide Mimetics of RRM proteins.

  • 200 potent inhibition of hiv replication by rna binding Peptide Mimetics with unprecedented specificity
    Journal of Biomolecular Structure & Dynamics, 2013
    Co-Authors: Gabriele Varani
    Abstract:

    RNA provides an inviting target for pharmaceutical intervention in both infectious and chronic diseases, but it has so far been impossible to identify drug-like molecules with sufficient potency to lead to the successful clinical applications. We have developed a new class of structurally constrained cyclic Peptides to target the interaction between the human immunodeficiency virus (HIV-1) transactivator protein Tat and its response element TAR (1,2), which plays an essential role in viral replication. Many previous attempts to inhibit this interaction have failed to yield molecules with sufficient potency and specificity to warrant pharmaceutical development. The peptidic mimics of Tat that are pM inhibitors of the Tat-TAR interaction and discriminate > 1000 fold between closely related RNAs. They are potent inhibitors of viral replication (tens of nM) with no cytotoxicity and efficient cell penetration which specifically inhibit TAR-dependent reverse transcription as well as activation of transcription,...

  • essential structural requirements for specific recognition of hiv tar rna by Peptide Mimetics of tat protein
    Nucleic Acids Research, 2011
    Co-Authors: Amy Davidson, Krystyna Patorakomisarska, John A Robinson, Gabriele Varani
    Abstract:

    The pharmacological disruption of the interaction between the HIV Tat protein and its cognate transactivation response RNA (TAR) would generate novel anti-viral drugs with a low susceptibility to drug resistance, but efforts to discover ligands with sufficient potency to warrant pharmaceutical development have been unsuccessful. We have previously described a family of structurally constrained β-hairpin Peptides that potently inhibits viral growth in HIV-infected cells. The nuclear magnetic resonance (NMR) structure of an inhibitory complex revealed that the Peptide makes intimate contacts with the 3-nt bulge and the upper helix of the RNA hairpin, but that a single residue contacts the apical loop where recruitment of the essential cellular co-factor cyclin T₁ occurs. Attempting to extend the Peptide to form more interactions with the RNA loop, we examined a library of longer Peptides and achieved > 6-fold improvement in affinity. The structure of TAR bound to one of the extended Peptides reveals that the Peptide slides down the major groove of the RNA, relative to our design, in order to maintain critical interactions with TAR. These conserved contacts involve three amino acid side chains and identify critical interaction points required for potent and specific binding to TAR RNA. They constitute a template of essential interactions required for inhibition of this RNA.

Jefferson Wright Tilley - One of the best experts on this subject based on the ideXlab platform.

  • carbacyclic Peptide Mimetics as vcam vla 4 antagonists
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Jefferson Wright Tilley, Gerry Kaplan, Nader Fotouhi, Barry A Wolitzky, Karen Rowan
    Abstract:

    Abstract Substitution of carbon for sulfur in a potent 13-membered cyclic disulfide containing Peptide was accomplished via an intramolecular Wittig reaction and resulted in a series of ‘carba’ analogues. Potency in the VCAM–VLA-4 assay was sensitive to ring size and lower than that of the parent disulfide.

  • cyclic thioether Peptide Mimetics as vcam vla 4 antagonists
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Nader Fotouhi, Jefferson Wright Tilley, Karen Rowan, Pramod V Joshi, Virginia Schwinge, Barry A Wolitzky
    Abstract:

    Selective substitution of a sulfur atom by carbon in a highly potent 13-membered cyclic disulfide was accomplished by intramolecular displacement of a bromide. The potency of the resulting thioethers in the VCAM/VLA-4 assay was dependant on ring size and the position of the sulfur atom.