Dipeptide mimetic of the nerve growth factor (NGF) loop 4, hexamethylenediamide
bis-(N-monosuccinyl- glutamyl-lysine) (GK-2), was synthesized at the V.V.
Zakusov Scientific Research Institute of Pharmacology of the Russian Academy of
Medical Sciences. GK-2 exhibited in vitro neuroprotective activity at nanomolar
concentrations, was efficient in animal models of the Parkinson’s disease,
ischemic and hemorrhagic stroke, and global cerebral ischemia at doses of
0.01–5 mg/kg (intraperitoneally) and 10 mg/kg (per os). The mnemotropic effects
of subchronic intraperitoneal administration of GK-2 on rat models of the
Alzheimer’s disease are described in this paper. Dipeptide GK-2 at a dose of 1
mg/kg is found to decrease the habituation deficit induced by the
septo-hippocampal pathway transsection and, at a dose of 0.5 mg/kg, to
significantly prevent spatial memory impairment in Morris water maze induced by
intracerebral injection of streptozotocin. Thus, GK-2, an original dipeptide
mimetic of NGF, acts on models of the Alzheimer’s disease upon systemic
administration.
The article is an overview of author’s data obtained in the framework of the project “The Creation of dipeptide preparations” at the V.V. Zakusov Institute of Pharmacology, Moscow, Russia. Advantages of dipeptides over longer peptides consist in that they are orally active owing to higher sta-bility and ability to penetrate biological barriers due to the presence of specific ATP–dependent trans-porters in enterocytes and blood-brain barrier. Two original approaches for dipeptide drugs design have been developed. Both of them are based on the idea of a leading role of central dipeptide fragment of the peptide chain beta-turn in the peptide-receptor interaction. The first approach, named “peptide drug-based design” represents the transformation of known nonpeptide drug into its dipeptide topological analog. The latter usually corresponds to a beta-turn of some regulatory peptide. The second approach represents the design of tripeptoide mimetic of the beta-turn of regulatory peptide or protein. The results of the studies, which led to the discovery of endogenous prototypes of the known non-peptide drugs piracetam and sulpiride, are presented herein. The paper discusses the process, based on the above-mentioned principles, that was used in designing of nontoxic, orally available, highly effective dipeptide drugs: nootropic noopept, dipeptide analog of piracetam; antipsychotic dilept, neurotensin tripeptoid analog; selective anxiolytic GB-115, tripeptoid analog of CCK-4, and potential neuroprotector GK-2, homodimeric dipeptide analog of NGF.
This study was performed in order to reveal the effect of Noopept (ethyl ester
of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding
activity of transcriptional factors (TF) in HEK293 cells transiently
transfected with luciferase reporter constructs containing sequences for CREB,
NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM)
was shown to increase the DNA-binding activity of HIF-1 only, while lacking the
ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and
HSF1. Noopept provoked an additional increase in the DNA-binding activity of
HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The
degree of this HIF-positive effect of Noopept was shown to be
concentration-dependent. Piracetam (1 mM) failed to affect significantly any of
the TF under study. The results of molecular docking showed that Noopept
(L-isomer), as well as its metabolite,
L-isomer of N-phenyl-acetylprolyl, unlike its
pharmacologically ineffective D-isomer, is able to bind to the
active site of prolyl hydroxylase 2. Taking into account the important role of
the genes activated by HIF-1 in the formation of an adaptive response to
hypoxia, data on the ability of Noopept to provoke a selective increase in the
DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and
pharmacological effects of Noopept revealed before. The obtained data allow one
to propose the HIF-positive effect as the primary mechanism of the activity of
this Pro-Gly-containing dipeptide.
The effects of endogenous dipeptide cycloprolyl-glycine on learning and memory in the model of postconvulsive retrograde amnesia of passive avoidance response in rats depended on the administration schedule. The dipeptide prevented retrograde amnesia, when injected prior to learning, had no effect after postlearning administration, and aggravated amnesia, when injected immediately before retrieval. These data suggest that cycloprolyl-glycine is similar to the standard nootropic piracetam by its mnemotropic activity.
Background:
NGF deficiency is one of the reasons for reduced β-cells survival in diabetes.
Our previous experiments revealed the ability of low-weight NGF mimetic, GK-2, to reduce hyperglycaemia
in a model of advanced diabetes. The increase in DNA damage in advanced diabetes was repeatedly
reported, while there were no data about DNA damage in the initial diabetes.
Aim:
The study aimed to establish whether DNA damage occurs in initial diabetes and whether GK-2
is able to overcome the damage.
Methods:
The early-stage diabetes was modelled in Balb/c mice by streptozotocin (STZ) (130 mg/kg,
i.p.). GK-2 was administered at a dose of 0.5 mg/kg, i.p., subchronically. The evaluation of DNA damage
was performed using the alkaline comet assay; the percentage of DNA in the tail (%TDNA) and
the percentage of the atypical DNA comets (“ghost cells”) were determined.
Results:
STZ at this subthreshold dose produced a slight increase in glycemia and MDA. Meanwhile,
pronounced DNA damage was observed, concerning mostly the percentage of “ghost cells” in the pancreas,
the liver and kidneys. GK-2 attenuated the degree of hyperglycaemia and reduced the % of “ghost
cells” and %TDNA in all the organs examined; this effect continued after discontinuation of the therapy.
Conclusion:
Early-stage diabetes is accompanied by DNA damage, manifested by the increase of
“ghost cells” percentage. The severity of these changes significantly exceeds the degree of hyperglycaemia
and MDA accumulation. GK-2 exerts an antihyperglycaemic effect and attenuates the degree
of DNA damage. Our results indicate that the comet assay is a highly informative method for search of
antidiabetic medicines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.