PMID- 24603864
OWN - NLM
STAT- MEDLINE
DCOM- 20150207
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 3
DP  - 2014
TI  - Combinatorial assembly of small molecules into bivalent antagonists of TrkC or 
      TrkA receptors.
PG  - e89617
LID - 10.1371/journal.pone.0089617 [doi]
LID - e89617
AB  - A library of peptidomimetics was assembled combinatorially into dimers on a 
      triazine-based core. The pharmacophore corresponds to beta-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.
FAU - Brahimi, Fouad
AU  - Brahimi F
AD  - Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
FAU - Ko, Eunhwa
AU  - Ko E
AD  - Department of Chemistry, Texas A&M University. Texas, United States of America.
FAU - Malakhov, Andrey
AU  - Malakhov A
AD  - Department of Chemistry, Texas A&M University. Texas, United States of America.
FAU - Burgess, Kevin
AU  - Burgess K
AD  - Department of Chemistry, Texas A&M University. Texas, United States of America.
FAU - Saragovi, H Uri
AU  - Saragovi HU
AD  - Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada; 
      Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, 
      Canada; Department of Oncology and the Cancer Center, McGill University, 
      Montreal, Quebec, Canada.
LA  - eng
GR  - T32 DE014318/DE/NIDCR NIH HHS/United States
GR  - P41 GM076261/GM/NIGMS NIH HHS/United States
GR  - R01 MH070040/MH/NIMH NIH HHS/United States
GR  - UL1 TR001120/TR/NCATS NIH HHS/United States
GR  - GM076261/GM/NIGMS NIH HHS/United States
GR  - MH070040/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140306
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Neurotrophin 3)
RN  - 0 (Peptidomimetics)
RN  - 0 (Small Molecule Libraries)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - EC 2.7.10.1 (Receptor, trkA)
RN  - EC 2.7.10.1 (Receptor, trkC)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/chemistry/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Combinatorial Chemistry Techniques/*methods
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Models, Chemical
MH  - Molecular Structure
MH  - NIH 3T3 Cells
MH  - Nerve Growth Factor/chemistry/pharmacology
MH  - Neurotrophin 3/chemistry/pharmacology
MH  - PC12 Cells
MH  - Peptidomimetics/chemical synthesis/chemistry/*pharmacology
MH  - Rats
MH  - Receptor, trkA/*antagonists & inhibitors/genetics/metabolism
MH  - Receptor, trkC/*antagonists & inhibitors/genetics/metabolism
MH  - Small Molecule Libraries/chemical synthesis/chemistry/*pharmacology
PMC - PMC3945644
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/03/08 06:00
MHDA- 2015/02/11 06:00
PMCR- 2014/03/06
CRDT- 2014/03/08 06:00
PHST- 2013/10/15 00:00 [received]
PHST- 2014/01/21 00:00 [accepted]
PHST- 2014/03/08 06:00 [entrez]
PHST- 2014/03/08 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
PHST- 2014/03/06 00:00 [pmc-release]
AID - PONE-D-13-42202 [pii]
AID - 10.1371/journal.pone.0089617 [doi]
PST - epublish
SO  - PLoS One. 2014 Mar 6;9(3):e89617. doi: 10.1371/journal.pone.0089617. eCollection 
      2014.