Dataset Information

Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers.

ABSTRACT: Alzheimer's disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid ? (A?) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic A? oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural ?-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind A? oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to A?, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor A? toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for A? binding.

SUBMITTER: Bartus E

PROVIDER: S-EPMC6222781 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers.

Bartus Éva É Olajos Gábor G Schuster Ildikó I Bozsó Zsolt Z Deli Mária A MA Veszelka Szilvia S Walter Fruzsina R FR Datki Zsolt Z Szakonyi Zsolt Z Martinek Tamás A TA Fülöp Livia L

Molecules (Basel, Switzerland) 20181002 10

Alzheimer's disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatur ...[more]

PMID: 30279351

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Project description:BACKGROUND: An approach to use multivalent dendrimer carriers for delivery of nucleoside signaling molecules to their cell surface G protein-coupled receptors (GPCRs) was recently introduced. RESULTS: A known adenosine receptor (AR) agonist was conjugated to polyamidoamine (PAMAM) dendrimer carriers for delivery of the intact covalent conjugate to on the cell surface. Depending on the linking moiety, multivalent conjugates of the N6-chain elongated functionalized congener ADAC (N6-[4-[[[4-[[[(2-aminoethyl)amino]carbonyl]methyl]anilino]carbonyl]methyl]phenyl]-adenosine) achieved unanticipated high selectivity in binding to the cytoprotective human A3 AR, a class A GPCR. The key to this selectivity of > 100-fold in both radioreceptor binding (Ki app = 2.4 nM) and functional assays (EC50 = 1.6 nM in inhibition of adenylate cyclase) was maintaining a free amino group (secondary) in an amide-linked chain. Attachment of neutral amide-linked chains or thiourea-containing chains preserved the moderate affinity and efficacy at the A1 AR subtype, but there was no selectivity for the A3 AR. Since residual amino groups on dendrimers are associated with cytotoxicity, the unreacted terminal positions of this A3 AR-selective G2.5 dendrimer were present as carboxylate groups, which had the further benefit of increasing water-solubility. The A3 AR selective G2.5 dendrimer was also visualized binding the membrane of cells expressing the A3 receptor but did not bind cells that did not express the receptor. CONCLUSION: This is the first example showing that it is feasible to modulate and even enhance the pharmacological profile of a ligand of a GPCR based on conjugation to a nanocarrier and the precise structure of the linking group, which was designed to interact with distal extracellular regions of the 7 transmembrane-spanning receptor. This ligand tool can now be used in pharmacological models of tissue rescue from ischemia and to probe the existence of A3 AR dimers.

Dataset Information

Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers.

Publications

Structural Optimization of Foldamer-Dendrimer Conjugates as Multivalent Agents against the Toxic Effects of Amyloid Beta Oligomers.

Similar Datasets

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