title: Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicinal Chemistry, V.V. Zakusov Institute of Pharmacology, Baltiyskaya str. 8, 125315, Moscow, Russia. tata-sosnovka@mail.ru.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Gudasheva
authors.affiliation: Department of Medicinal Chemistry, V.V. Zakusov Institute of Pharmacology, Baltiyskaya str. 8, 125315, Moscow, Russia. povarnina@gmail.com.
authors.forename: Polina Yu
authors.initials: PY
authors.lastname: Povarnina
authors.affiliation: Laboratory of Neuroprotective Pharmacology, V.V. Zakusov Institute of Pharmacology, Baltiyskaya str. 8, 125315, Moscow, Russia. zenina_tatyana@mail.ru.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Antipova
authors.affiliation: Department of Medicinal Chemistry, V.V. Zakusov Institute of Pharmacology, Baltiyskaya str. 8, 125315, Moscow, Russia. yulia.firsova@gmail.com.
authors.forename: Yulia N
authors.initials: YN
authors.lastname: Firsova
authors.affiliation: Laboratory of Pharmacological Regulation of Alcohol and Drug Addiction, V.V. Zakusov Institute of Pharmacology, Baltiyskaya str. 8, 125315, Moscow, Russia. makonstant.24@mail.ru.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Konstantinopolsky
authors.affiliation: Department of Pharmacogenetics, V.V. Zakusov Institute of Pharmacology, Baltiyskaya str. 8, 125315, Moscow, Russia. seredeninpharm@mail.ru.
authors.forename: Sergey B
authors.initials: SB
authors.lastname: Seredenin
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D020932:Nerve Growth Factor / Q000737:chemistry*; D016716:PC12 Cells; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D004151:Dipeptides; D020932:Nerve Growth Factor; D011505:Protein-Tyrosine Kinases