Open Access
Journal of Biomedical Science, volume 22, issue 1, publication number 106
Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction
Gudasheva Tatyana A
1
,
Povarnina Polina Yu
1
,
Firsova Yulia N
1
,
Konstantinopolsky Mark A
3
,
Seredenin Sergey B.
4
2
Publication type: Journal Article
Publication date: 2015-12-01
Journal:
Journal of Biomedical Science
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 11
ISSN: 10217770, 14230127
Molecular Biology
General Medicine
Cell Biology
Clinical Biochemistry
Pharmacology (medical)
Endocrinology, Diabetes and Metabolism
Biochemistry (medical)
Abstract
This study aimed at developing nerve growth factor (NGF) mimetics that selectively activate specific biological signals and, as a result, lack the side effects of the full-length protein. Two dimeric dipeptides, bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6) and bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), were designed based on the most exposed outside fragments of NGF, namely, the loop 1 and loop 4 β-turn sequences, respectively. These dipeptides exhibited neuroprotective activity in vitro at micro-nanomolar concentrations. Studies on the mechanism of action revealed that both compounds elevate the level of tyrosine kinase A (TrkA) receptor phosphorylation and that they each have different postreceptor signaling patterns. GK-6 increases the levels of extracellular signal-regulated kinase (ERK) and AKT kinase phosphorylation, whereas GK-2 only increases the level of AKT phosphorylation. Apart from the neuroprotective activity, GK-6 promoted differentiation in PC12 cells, whereas GK-2 did not. Furthermore, it was established that the neuroprotective activity of GK-2 was completely abolished by a selective inhibitor of phosphatidylinositol 3-kinase (LY294002) but not by a specific inhibitor of mitogen-activated protein kinases MEK1 and MEK2 (PD98059). In vivo experiments demonstrated that GK-2 did not induce hyperalgesia, which is one of the primary adverse effects of NGF. By contrast, GK-6 produced a significant decrease in the pain threshold of rats as determined by the tail flick test. The data obtained suggest that dimeric dipeptide NGF mimetics are promising candidates in the development of pharmacological agents with NGF-like activity that are free of the main side effect of NGF.
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Gudasheva T. A. et al. Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction // Journal of Biomedical Science. 2015. Vol. 22. No. 1. 106
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Gudasheva T. A., Povarnina P. Yu., Antipova T. A., Firsova Y. N., Konstantinopolsky M. A., Seredenin S. B. Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction // Journal of Biomedical Science. 2015. Vol. 22. No. 1. 106
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TY - JOUR
DO - 10.1186/s12929-015-0198-z
UR - https://doi.org/10.1186%2Fs12929-015-0198-z
TI - Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction
T2 - Journal of Biomedical Science
AU - Gudasheva, Tatyana A
AU - Povarnina, Polina Yu
AU - Antipova, Tatyana A
AU - Firsova, Yulia N
AU - Konstantinopolsky, Mark A
AU - Seredenin, Sergey B.
PY - 2015
DA - 2015/12/01 00:00:00
PB - Springer Nature
IS - 1
VL - 22
SN - 1021-7770
SN - 1423-0127
ER -
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@article{2015_Gudasheva,
author = {Tatyana A Gudasheva and Polina Yu Povarnina and Tatyana A Antipova and Yulia N Firsova and Mark A Konstantinopolsky and Sergey B. Seredenin},
title = {Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction},
journal = {Journal of Biomedical Science},
year = {2015},
volume = {22},
publisher = {Springer Nature},
month = {dec},
url = {https://doi.org/10.1186%2Fs12929-015-0198-z},
number = {1},
doi = {10.1186/s12929-015-0198-z}
}
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