Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.

A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3), nerve growth factor (NGF), or brain-derived neurotrophic factor (BDNF). These are the natural ligands for...

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Autores principales:	Fouad Brahimi, Eunhwa Ko, Andrey Malakhov, Kevin Burgess, H Uri Saragovi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1d45cf5a339440e39a7fc017f9cb33fe
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spelling	oai:doaj.org-article:1d45cf5a339440e39a7fc017f9cb33fe2021-11-18T08:29:20ZCombinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.1932-620310.1371/journal.pone.0089617https://doaj.org/article/1d45cf5a339440e39a7fc017f9cb33fe2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24603864/?tool=EBIhttps://doaj.org/toc/1932-6203A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3), nerve growth factor (NGF), or brain-derived neurotrophic factor (BDNF). These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f) are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b) are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.Fouad BrahimiEunhwa KoAndrey MalakhovKevin BurgessH Uri SaragoviPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e89617 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fouad Brahimi Eunhwa Ko Andrey Malakhov Kevin Burgess H Uri Saragovi Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.
description	A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3), nerve growth factor (NGF), or brain-derived neurotrophic factor (BDNF). These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f) are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b) are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.
format	article
author	Fouad Brahimi Eunhwa Ko Andrey Malakhov Kevin Burgess H Uri Saragovi
author_facet	Fouad Brahimi Eunhwa Ko Andrey Malakhov Kevin Burgess H Uri Saragovi
author_sort	Fouad Brahimi
title	Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.
title_short	Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.
title_full	Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.
title_fullStr	Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.
title_full_unstemmed	Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.
title_sort	combinatorial assembly of small molecules into bivalent antagonists of trkc or trka receptors.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/1d45cf5a339440e39a7fc017f9cb33fe
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Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.

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