2'-5'-Oligoadenylates as a «tool» of innate immunity
It is a matter of common knowledge, that «core» 2'-5'-oligoadenylates and their analogues posses broader biological activity than it can be predicted within the traditional «interferon» hypothesis. They exhibit immunomodulatory effects and are effective immunosuppressive agents upon organ...
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Інститут молекулярної біології і генетики НАН України
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| Cite this: | 2'-5'-Oligoadenylates as a «tool» of innate immunity / Z.Yu. Tkachuk // Вiopolymers and Cell. — 2013. — Т. 29, №. 4. — С. 266-276. — Бібліогр.: 61 назв. — англ. |
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| citation_txt | 2'-5'-Oligoadenylates as a «tool» of innate immunity / Z.Yu. Tkachuk // Вiopolymers and Cell. — 2013. — Т. 29, №. 4. — С. 266-276. — Бібліогр.: 61 назв. — англ. |
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| description | It is a matter of common knowledge, that «core» 2'-5'-oligoadenylates and their analogues posses broader biological activity than it can be predicted within the traditional «interferon» hypothesis. They exhibit immunomodulatory effects and are effective immunosuppressive agents upon organ and tissue transplantation. Oligoadenylates render antiviral activity against a wide range of viruses both DNA and RNA origin. These drugs regulate apoptosis, cell proliferation and possess antitumor activity. Such polyvalent activity is based on their ability to bind signaling proteins, slightly altering their conformation and modulating their activity. They can also change the secondary structure of both viral DNA and RNA, making them accessible for enzymatic cleavage. The hypothesis forwarded within this review is aimed at making an attempt to explain the mechanism of 2'-5'-oligoadenylates antiviral action. Our recent papers, containing experimental data to support this hypothesis, are discussed in this review.
Відомо, що «кори» 2'-5'-олігоаденілатів та їхніх аналоги володіють значно ширшою біологічною активністю, ніж це можна передбачити в рамках традиційної «інтерферонової» гіпотези. Вони проявляють імуномодулюючу дію і є ефективними імуносупресорами при трансплантації органів і тканин. Олігоаденілатам притаманна противірусна активністю стосовно широкого спектра як ДНК-, так і РНК-вмісних вірусів. Ці препарати регулюють апоптоз і проліферацію клітин та володіють протипухлинною активністю. Така полівалентна активність олігоаденілатів базується на можливості зв’язуватися з сигнальними білками, що призводить до зміни їхньої конформації та модуляції активності. Вони також можутьпорушувати вторинну структуру вірусних ДНК і РНК і роблять їх доступними для розщеплення клітинними ферментами. Запропоновано гіпотезу, яка пояснює механізм противірусної дії 2'-5'-олігоаденілатів, а також наведено експериментальні дані на її користь.
Известно, что «коры» 2'-5'-олигоаденилатов и их аналоги обладают более широкой биологической активностью, чем это можно предположить в рамках традиционной «интерфероновой» гипотезы. Они проявляют иммуномодулирующее действие и являются эффективными иммуносупрессорами при трансплантации органов и тканей. Олигоаденилатам присуща антивирусная активность относительно широкого спектра как ДНК-, так и РНК- содержащих вирусов. Эти препараты регулируют апоптоз и пролиферацию клеток и обладают противоопухолевой активностью. Такая поливалентная активность олигоаденилатов базируется на возможности связываться с сигнальными белками, что приводит к изменению их конформации и модуляции активности. Они также могут нарушать вторичную структуру вирусных ДНК и РНК и делать их доступными для расщепления клеточными ферментами. Предложена гипотеза, объясняющая механизм противовирусного действия 2'-5'-олигоаденилатов, и приведены экспериментальные данные в ее пользу.
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UDC 615.281
2'-5'-Oligoadenylates as a «tool» of innate immunity
Z. Yu. Tkachuk
Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnogo Str., Kyiv, Ukraine, 03680
ztkachuk@bigmir.net
It is a matter of common knowledge, that «core» 2'-5'-oligoadenylates and their analogues posses broader biolo-
gical activity than it can be predicted within the traditional «interferon» hypothesis. They exhibit immunomodu-
latory effects and are effective immunosuppressive agents upon organ and tissue transplantation. Oligoadeny-
lates render antiviral activity against a wide range of viruses both DNA and RNA origin. These drugs regulate
apoptosis, cell proliferation and possess antitumor activity. Such polyvalent activity is based on their ability to
bind signaling proteins, slightly altering their conformation and modulating their activity. They can also change
the secondary structure of both viral DNA and RNA, making them accessible for enzymatic cleavage. The hypo-
thesis forwarded within this review is aimed at making an attempt to explain the mechanism of 2'-5'-oligoadeny-
lates antiviral action. Our recent papers, containing experimental data to support this hypothesis, are discussed
in this review.
Keywords: 2'-5'-oligoadenylate, 2'-5'-oligoadenylatsyntase, interferon a, protein kinases, Ca
2+
-binding proteins,
RNA-, DNA- containing viruses.
At the end of the seventies Ian Kerr initiated the study
on the 2'-5'-adenylate system (2'-5'-A) of the general
formula pppA(2'pA)An (n = 1–3) and drew attention to
its role in initiation of a metabolic pathway inhibiting
intracellular viral replication [1]. The 2'-5'-A system
plays an important role in the cascade of interferon
(IFN)-induced biochemical reactions [2]. It was at that
time that the action of 2'-5'-oligoadenylates on regula-
tion of cell growth, oncogene expression, cellular diffe-
rentiation, and their role in cellular response to changes
in hormonal milieu was established. 2'-5'-oligoadeny-
lates inhibit DNA synthesis in different cell cultures
[3], exhibit anti-mutagenic properties [4] and influence
the natural killer cell activity [5]. 2'-5'-A3 core analogs
also exert a wide range of biological actions [6]. Sum-
marizing the advances in the study of 2'-5'-oligoadeny-
lates in the mid-eighties, the leading American newspa-
per, The Wall Street Journal, reported that the one who
would unravel the mechanism of antiviral action of 2'-
5'-oligoadenylates, would be capable of synthesizing a
broad spectrum antiviral agent comparable to «antivi-
ral penicillin».
IFN is capable to induce 2'-5'-oligoadenylate syn-
thetase (2'-5'-OAS) activity, that in the presence of doub-
le-stranded (ds) RNA converts ATP into 2'-5'-linked oli-
gomers of adenosine with the general formula pppA
(2'p-5'A)n. Experimental findings demonstrate that this
biochemical reaction cascade is the key mechanism of
antiviral IFN properties: ppp(2'-5')An can bind to and
activate the latent RNase L which degrades viral and
cellular RNA. The 2'-5'-OAS/RNase L pathway plays a
pivotal role in the innate antiviral immunity. This is the
pathway by which RNase L destroys viral RNA and cel-
lular mRNAs regardless of their origin. Its function is
maintained by IFNs, cytokines, a number of signalling
proteins, including protein kinases and Ca2+-binding
proteins. As it will be further discussed, oligoadenyla-
tes are not only involved in antiviral immunity, but also
may effectively suppress allograft rejection and mediate
antitumour immunity. Phosphorylated oligoadenylate
ppp(2'-5'-)An is actively metabolized in cells and is clea-
ved by 2'-phosphodiestherase or 5'-phosphatase. In the
266
ISSN 0233–7657. Biopolymers and Cell. 2013. Vol. 29. N 4. P. 266–276 doi: 10.7124/bc.000821
� Institute of Molecular Biology and Genetics, NAS of Ukraine, 2013
267
2'-5'-OLIGOADENYLATES AS A «TOOL» OF INNATE IMMUNITY
latter case, it is converted to a 5'-diphosphorylated core
(2'-5'-An).
Oligoadenylates have been found in almost all euka-
ryotic cells. The range of their intracellular concen-
tration is wide, depending on the functional specificity
of a cell, the phase of the cell cycle. Intracellular con-
centration of oligoadenylates also changes in case of vi-
ral infection. The normal 2'-5'-A intracellular concen-
tration is below 1 nM. It can increase dozens of times
and reach 10 nM in case of 2'-5'-OAS induction by IFN
or a virus [7].
Analogs of 2'-5'-An (n = 3) also possess a number of
biological properties, and, therefore, are of conside-
rable interest as well [8]. Based on the example of 2'-5'-
A3 analogs including well-known antimetabolites 9-(be-
ta-D-xylofuranosyl) adenine 2'-5'-A3l-epoxy and 3'-de-
oxyadenosine 2'-5'-A3cord in their structure, it has been
shown that they exhibit activity against the type 1 and
type 2 herpes virus. Under the influence of cellular phos-
phodiesterase, the core trimmers are hydrolyzed to the
respective nucleoside-5'monophosphates and nucleosi-
des with their characteristic activity [9].
On the other hand, it has been shown quite con-
vincingly that 2'-5'-A3 and their analogs exhibit their
own characteristic activity as trimmeric compounds [10].
It should be emphasized that these core trimmers mimic
many of the IFN effects in the cells [8, 9].
The advantage of the use of 2'-5'-A3 oligoadenylate
analogs is related to their biological activity. They
break down slowly under the influence of phosphodies-
therase and maintain a long-lasting activity as compa-
red with T-lymphocytes (about 2 weeks). They are easi-
ly synthesized in large quantities with the help of the
readily available chemical synthetic techniques [11].
Since they are the analogs of the natural products,
when used in effective dosages they show little or no toxic
activity and exhibit no adverse effects on other impor-
tant functions of the organism. Normally, three compo-
nent analogs of 2'-5'-A3 oligoadenylates, used singly or
in a combination, are used with modifications in ribose
positions 2' and 3' of the third terminal adenosine moiety.
The identified biological properties of «core» 2'-5'-
A3 and their analogues allowed us to make assumption
about their ability to affect the structure and function of
a wide range of antiviral immunity proteins. Accoding
to this hypothesis we performed our studies.
Immunomodulating properties. As in vivo phos-
phodiesterases hydrolyze 2'-5'-A3 to simple compounds
(adenosine and adenosine-5'-monophosphate), we pro-
posed a new method, and synthesized 2'-5'-A3 analogs
which were found to be more resistant to the action of
phosphodiesterases (Figure). Subsequently, we selec-
ted the most active analogs. The most promising ana-
logs appeared to be 9-(2,3-anhydro-beta-D-ribofurano-
syl) adenine (2'-5'-A3epoxy) and 9-(2,3-anhydro-beta-
D-lyxofuranosyl) adenine (2'-5'-A3l-epoxy) [12]. Both
analogues were found to be resistant to the action of sna-
ke venom phosphodiesterase. For example, 2'-5'-A3epo-
xy appeared to be 35-fold more resistant as compared
with its prototype 2'-5'-A3 [13].
Immunomodulating properties of core 2'-5'-A3 and
their analogs were studied on a model of a delayed-type
hypersensitivity reaction (DTHR). 2'-5'-A3 was found
to exhibit the most potent immunostimulating effect,
while its analog 2'-5'-A3epoxy, on the contrary, inhibi-
ted DTHR. The effect was dependent on the concen-
tration of a cytostatic agent, thiophosphamide. Other
analogs, such as 2'-5'-A3epoxy, 2'-5'-A3 (xylose and ara-
binose derivatives) were not found to possess any im-
munosuppressive action. 2'-5'-A3epoxy, in contrast to
the natural 2'-5'-A3, exhibited a much more marked ac-
tion upon blast-transformation reaction of lymphocytes
both in vitro and in vivo. Therefore, 2'-5'-A3 was conclu-
ded to possess immunostimulating properties, while its
analog 2'-5'-A3epoxy was found to have immunosup-
pressive properties [14].
Further studies of 2'-5'-A3 analogs have shown that
2'-5'-A3epoxy and 2’-2'-5'-A3l-epoxy exhibit a potent
immunosupressive action specifically aimed against T-
killer and T-helper cells. A single injection of 2'-5'-
A3epoxy suppresses in vivo the number of T-killers and
T-helpers by 50 % within 48 h. Comparative analysis of
the activity of different analogs showed that 2'-5'-A3
epoxy was more resistant to the action of phosphodi-
esterase than 2'-5'-A3l-epoxy and suppressed more acti-
vely the number of T-killer and T-helper cells [15].
Therefore, in further experiments 2'-5'-A3epoxy was
used as an immunosuppressor in animal models of re-
nal transplantation. In rabbits, injections of 2'-5'-A3
epoxy provided normal functioning of the kidney trans-
plant for a period of 3 months. T-lymphocyte blast-trans-
formation in post-transplanted rabbits stimulated with
Concavalin A was suppressed by almost 10-fold [12].
In monkeys, intravenous administration of 2'- 5'-A3epo-
xy protected the transplant against rejection, and pro-
moted the recovery of function of the transplanted kid-
ney. A dose-dependent response was found to the action
of 2'-5'-A3epoxy upon the number of T- killer and T-hel-
per cells in the blood of transplanted animals and ele-
vated levels of �- and �-interferons, which are markers
of antiviral and antibacterial protection [12–15].
Therefore, 2'-5'-A3epoxy may be used as an immu-
nosuppressive agent in transplantation of kidneys, heart,
lungs, bone marrow and other organs. It can be also used
in the treatment of T-cell-mediated immune disorders,
in autoimmune diseases, and in lymphocytic tumors.
Antiviral action. Biological activity of 2'-5'-A3
and their analogs was studied on different groups of vi-
ruses. 2'-5'-A3xylo has been shown to possess a poten-
tial antiviral activity against Herpes simplex type 1 and
type 2 virus [9], and 2'-5'-A3 has inhibited viral mRNA
synthesis, without action upon the growth of non-infec-
ted by Herpes simplex virus cells [16]. 2'-5'-A3 inhibi-
ted replication of the virus Sindbis and vesicular sto-
matitis virus in a human angioma cell culture [17]. 2'-
5'-A3 analogs proved to be effective as inhibitors of re-
production of retroviruses. A 2'-5'-A3 analog, contai-
ning 3'-cordycepin instead of 2'-5'-A3cord was found
to inhibit HIV-1 reverse transcriptase [18].
We studied the antiviral activity of 2'-5'-A3 and their
analogs on a phage � model. These agents were shown
to induce self-destruction of the phage� DNA, thus eli-
minating its infectivity [19]. The effect of core 2'-5'-A3
upon the enzymes of nucleic acids metabolism was also
studied. EcoRI, BamHI and HindIII restrictases in the
presence of some 2'-5'-A3 were shown to be inhibited,
as well as to cause the loss of site specificity of the pha-
ge� DNA and to alter the restrictase functional activity.
In the latter case they act as non-specific DNAses. This
effect depends on the structure of 2'-5'-A3, its concent-
ration and restrictase type. Cordycepin analog of 2'-5'-A3
was ten times more effective as compared with the natu-
ral core [20].
Subsequently, we studied the characteristics of the �
phage native DNA hydrolysis by S1 nuclease in the pre-
sence of 2'-5'-A3 and their analogs. Incubation of 2'-5'-A3
with the native [3H]-thymidine-labled DNA of phage� re-
sults in formation of a large number of portions of single-
stranded DNA� available for hydrolysis. The degree of
hydrolysis depended on 2'-5'-A3 concentration and its
structure. Nucleotides and nucleosides did not exhibit
that type of activity. Two- and four-member «cores» 2'-
5'-A and their analogs had a weaker effect upon the se-
condary DNA structure. These data permit to assume that
2'-5'-A3 influences the secondary DNA� structure, pro-
moting thus the formation of single-stranded portions
268
TKACHUK Z. Yu.
N
N N
N
NH2
OHO
HO
O
HO
N
N N
N
NH2
O
O
N
N N
N
NH2
O
P
O
�
O O
O
P
O
�
O
OHOH
N
N N
N
NH2
OHO
HO
O
HO
N
N N
N
NH2
O
O
N
N N
N
NH2
O
P
O
�
O O
O
P
O
�
O
OH
N
N N
N
NH2
OHO
HO
O
HO
N
N N
N
NH2
O
O
N
N N
N
NH2
O
P
O
�
O O
O
P
O
�
O
O
N
N N
N
NH2
OHO
HO
O
HO
N
N N
N
NH2
O
O
N
N N
N
OH
O
P
O
�
O O
O
P
O
�
O
OHOH
N
N N
N
NH2
OHO
HO
O
HO
N
N N
N
NH2
O
O
N
N N
N
NH2
O
P
O
�
S O
O
P
O
�
S
OHOH
N
N N
N
NH2
OHO
HO
O
HO
N
N N
N
NH2
O
O
N
N N
N
NH2
O
P
O
�
O O
O
P
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�
O
OHOH
NH2
2'-5'-A3epoxy 2'-5'-A3cord
2'-5'-A3amino 2'-5'-A3ino 2'-5'-A3thio
2'-5'-A3
Structures of 2'-5'-A
3
and its
analogues
which can be cleaved by S1 nuclease. This phenome-
non can not be explained by activation of nuclease S1 by
2'-5'-A3, as inhibition of hydrolysis was demonstrated
when melted DNA was used in the same conditions [21].
Stacking effect has been observed with 2'-5'-oligo-
adenylates, especially with 2'-5'-A3. Stacking characte-
ristics of 2'-5'-A3 presumably provide the action upon
the DNA structure in a way resulting in formation of
single-stranded portions. The influence of 2'-5'-A3 and
their two- and four-member analogs upon the secon-
dary structure of polynucleotides was studied with the
help of a micro calorimetric method. The obtained re-
sults on a model of RNA- and DNA-like polynucleo-
tides confirm our suggestion that the action of 2'-5'-A3
cores is aimed at alteration of the secondary structure of
nucleic acids. Moreover, the study of synthetic polynuc-
leotides confirms the possibility of immediate interac-
tion of 2'-5'-A3 with nucleic acids. It is important that
only three-member 2'-5'-A3 are capable to alter the poly-
nucleotide structure [22].
The capacity of 2'-5'-A3 to get delivered inside the
cell and to influence the secondary DNA structure was
studied on a model of a fibroblast cell culture. The la-
beled core 3H-2'-5'-A3 was shown to bind to fibroblast
cells in low concentrations, and this process appeared
to depend on the incubation time. Analysis of unbound
3H-2'-5'-A3 in a suprasediment fluid showed that only 2
to 4 per cent of 2'-5'-A3 gets delivered to cells.
The possible influence of exogenous 2'-5'-A3 on in-
tracellular DNA was studied by assessment of the chan-
ge of DNA structure, using fluorescent propidium iodi-
de. Incubation of 2'-5'-A3 with fibroblast cells yielded a
general increase of fluorescence intensity up to 20 %.
Hence 2'-5'-A3, when delivered inside the cell, may in-
crease the number of propidium iodide binding sites.
To study the possible damage of intracellular fibro-
blast DNA by 2'-5'-A3, fibroblasts were treated with
nuclease S1. As nuclease S1 is active against single-
stranded DNA, it was hypothesized that interaction of
2'-5'-A3 with cellular DNA results in formation of sing-
le-stranded DNA portions, subject to hydrolysis by the
enzyme. Incubation of fibroblast cells with 2'-5'-A3 and
nuclease S1 resulted in a significant decrease of fluores-
cence intensity. Therefore we suggested that double-
stranded nucleic acids may be one of the intracellular
targets of 2'-5'-A3 [23].
In summary, experiments with S1 nuclease and pha-
ge� DNA as well as with fibroblast cell culture demonst-
rated that 2'-5'-A3 may influence the structure of a doub-
le-stranded DNA. These effects are observed even if de-
livery of 2'-5'-A3 inside the cells is relatively low. It can
be suggested that antimitogenic and antiviral properties
(including those against DNA viruses) may be associa-
ted with immediate action upon a double-stranded struc-
ture of nucleic acids, beyond the action of RNase L.
Thus, the action of 2'-5'-A3 cores (the synthesis of which
is induced by IFN system) is possibly aimed at altera-
tion of the secondary structure of the viral nucleic acids,
causing their rapid destruction by cellular nucleases re-
gardless of the virus origin.
It is noteworthy, however, that the antiviral effect of
IFN is associated with the antiviral action of IFN-
induced ppp2'-5'-An, although not in all cases. This per-
mits to suggest that there may be other yet undiscove-
red mechanisms of antiviral action of 2'-5'-oligoade-
nylates. We studied the antiviral action of 2'-5'-A3epo-
xy, in particular its action upon HIV-1 reproduction,
interferonogenic activity, and action upon reverse trans-
criptase activity of both exogenous and endogenous re-
troviruses. Pretreatment with 2'-5'-A3 and 2'-5'-A3 epo-
xy was shown to be associated with a decrease of HIV
infectivity due to an increase of IFN concentration, as
well as with suppression of reverse trancriptase activity
of HIV and Moloney murine leukemia virus. The study
of kinetics of reverse transcriptase inhibition by 2'-5'-A3
and its epoxy analog proved them to be non-competi-
tive reverse transcriptase inhibitors of both retroviruses
[24].
We further studied the antiviral action of 2'-5'-A3
and its analogs on RNA-containing swine transmissib-
le gastroenteritits virus and Aujeszky disease virus. 2'-
5'-A3 and 2'-5'-A3epoxy were shown to lower the titer
of varicella vaccine virus by more than 2,5 lg TCD (tis-
sue cytopathic doses). The study of action of 2'-5'-A3,
2'-5'-A3epoxy, and 2'-5'-A3xylo on reproduction of swi-
ne transmissible gastroenteritits virus and Aujeszky di-
sease virus showed that they have different modes of ac-
tion. In particular, in case of Aujeszky disease virus
which belongs to a herpesviridae family, 2'-5'-A3 is of
potential interest as it appeared to lower the virus titer
by 1,77 lg TCD. In case of swine transmissible gastroen-
teritits virus, 2'-5'-A3epoxy was found to be the most ac-
269
2'-5'-OLIGOADENYLATES AS A «TOOL» OF INNATE IMMUNITY
tive. This finding indicates the potential advantages its
use against corona viruses. 2'-5'-A3epoxy exhibited the
antiviral effect regardless of the mode of its delivery in-
to the cell, while 2'-5'-A3xylo did not exhibit any antivi-
ral effect on the above-mentioned viruses. The obtai-
ned results, therefore, permit to suggest that the studied
olygoadenylates realize their antiviral properties on dif-
ferent groups of viruses [25].
Antitumor action. 2'-5'-A are intracellular media-
tors of not only IFN, but also of a number of different
cytokines. In particular, 2'-5'-A-synthetase stimulation
is observed under the action of epidermal growth fac-
tor, tumor necrosis factor [26] interleukins 1 and 6 [27,
28], and transforming growth factor � [29] upon the
cells. Induction of 2'-5'-A system activity is seen not
only in viral infections, but also in other pathological
states of the organism: type 1 diabetes mellitus [27],
chronic fatigue syndrome [30], and in heat shock [31].
In the recent years significant progress has been achie-
ved in the study of action of these substances upon nor-
mal and transformed nervous cells. In particular, 2'-5'-
A3 has been shown to be able to induce the differen-
tiation of neuroblastoma cells [32] and myoblasts [33].
Another analog, 2'-5'-A3ether, inhibited the prolifera-
tion of transformed breast cells [34] .
It is evident that 2-5A and their analogs have a high
biological activity; therefore, we studied their antiproli-
ferative action. The influence of 2'-5'-A3epoxy in vitro
on cultivated cells of human neuroblastoma was studied.
2'-5'-A3epoxy was shown to decrease the number of cul-
tivated cells and to increase the protein content as com-
pared with control. Na, K+- and Ca2+, Mg2+-ATP-ase ac-
tivity in a microsomal fraction obtained from cells culti-
vated in presence of 2'-5'-A3epoxy, was shown to be
twofold lower than in the control cells. The obtained re-
sults confirm that 2'-5'-A3epoxy possesses antiprolifera-
tive activity and modulates significantly the activity of
Na+, K+- and Ca2+, Mg2+-ATP-ases. The processes of
normal cellular growth and division are known to de-
pend on the concentration gradients of Na+, K+, Mg2+
and Ca2+ ions. This permits to suggest that significant
decrease in Na+, K+- and Ca2+, Mg2+-ATP-ase activity
observed in our experiments is one of the major factors
contributing to antiproliferative effect of 2'-5'-A3epo-
xy. 2'-5'-A3epoxy may be regarded as substances with a
significant potential for their use in pharmacological
therapy of neurogenic tumors [35]. 2'-5'-A3 was demon-
strated to be able to modulate significantly the ion trans-
port mechanisms in human neuroblastoma cells [36].
Further studies of the action of �2b-IFN and of 2'-
5'-oligoadenylates upon the cultivated in vitro human
neuroblastoma cells confirmed the one-way action of
IFN, 2'-5'-A3 and 2'-5'-A3epoxy within the cell. Both
�2b-IFN and 2'-5'-oligoadenylates inhibit cellular proli-
feration, increase the intracellular protein content, mo-
dulate the sodium and calcium transport mechanisms
[37]. The one-way action of IFN and of oligoadeny-
lates was confirmed by the other investigators who stu-
died the antiproliferative effect of these agents in con-
canavalin A-stimulated murine lymphocytes [38]. Two
hypotheses were proposed to explain this phenomenon.
According to the first hypothesis 2'-5'-A3 when delive-
red inside the cell, gets phosphorylated by the kinases
present inside, and acts as ppp2'-5'-A3 [39]. According
to the second hypothesis, 2'-5'-A3 competitively inhibits
ppp2'-5'-A3 hydrolysis [40]. According to both hypothe-
ses the intracellular content of ppp2'-5'-A3 increases.
However, these both hypotheses do not take into consi-
deration the fact that IFN, in contrast to ppp2'-5'-A3,
activates the Jak/STAT signaling pathway through bin-
ding with specific superficial receptors, resulting in the
signal transduction from the cell receptor to nucleus and
activation of the early response genes, including the ge-
ne of 2'-5'-oligoadenylate synthetase. Transfection of
ppp2'-5'-A3 in physiological concentrations into a cell
was shown to cause induction of certain genes, inclu-
ding IFN-stimulated genes [41]. Probably, this discove-
ry explains the mechanism of the one-way action of IFN
and 2'-5'-A3. Most likely, they can influence the gene
expression of the innate immunity by mimicking the ef-
fects of one another.
Proliferation, apoptosis and migration of bone
marrow cells. After the discovery of the role of stem
cells in homeostasis of the organism, an intensive study
of agents capable of stimulating bone marrow stem cell
proliferation (BMC) in sub endosteal area was initia-
ted. We investigated the influence of 2'-5'-A3 agents
and their analogs on stem cells content of blood. The
natural 2'-5'-A3 core and its analog 2'-5'-A3epoxy were
shown to inhibit apoptotic processes in the studied cells
and stimulate BMC proliferation by approximately 2-
fold as compared with control. However, 2'-5'-A3epoxy
270
TKACHUK Z. Yu.
differs from the natural core by exhibiting a somewhat
higher activity with regard to apoptotic and prolifera-
tive processes of BMC. The influence of 2'-5'-A3 and
2'-5'-A3epoxy on migration of stem BMC in mice after
syngenic transplantation was also investigated. 2'-5'-A3
and 2'-5'-A3epoxy were found to stimulate the migra-
tion of stem BMC almost 2-fold as compared with cont-
rol. The 10-fold decrease of concentration of these
agents did not affect significantly the migration of stem
BMC, and, respectively, the number of spleen colonies
in the recipient mice [42].
The influence of 2'-5'-A on cellular regulatory
systems. The proliferative action of 2'-5'-A cores and
their analogs is supposedly associated with activation
of the cAMP system, manifesting as the change of inter-
cellular cAMP level [43]. Considering the strong inter-
relationship and interdependence between 2'-5'-A and
cAMP systems, we evaluated the association between
the action of 2'-5'-A analogs upon cell cultures and ani-
mal organs, on one side, and concentrations of cAMP
and cGMP in these cells and tissues, on the other side.
Incubation of T-lymphocytes with 2'-5'-A3epoxy was
shown to be associated with an increase of cAMP levels,
while 2'-5'-A3 decreased cAMP levels by approxima-
tely 2-fold [44].
In experiments in vivo after administration of 2'-5'-A3-
epoxy after 1 hour the plasma level of cAMP was obser-
ved increased 2-fold, as compared with the control. As
for natural 2'-5'-A3, it failed to change the levels of cAMP
and cGMP in blood plasma samples. Administration of
2'-5'-A3epoxy resulted in almost 2-fold increase of cAMP
levels in the mouse liver. Similar experiments with eva-
luation of spleen showed other results. 2'-5'-A3epoxy
and 2'-5'-A3 caused 2–2.5-fold lowering of cAMP, whi-
le cGMP level remained the same as it was in the liver.
Therefore, 2'-5'-A3 analogs, in contrast to natural 2'-5'-A3,
when introduced into animal organs and tissues, influen-
ce the cAMP levels in a concentration-dependent man-
ner, and do not affect the cGMP levels [44].
The action of inductors of proliferation and of cyclic
nucleotides is known to depend on the concentration of
the Ca2+ ions [45]. As the 2'-5'-A system is related to
cAMP, it can be hypothesized that a stimulating action
of 2-5A and their analogs depends on the intracellular
calcium metabolism. Similar mechanisms are involved
in the function of arterial smooth muscle cells. Thus,
the aim of our study was to investigate a possible role
of core 2'-5'-A3 and 2'-5'-A3epoxy in the mechanism of
regulation of smooth muscle cells of the aorta and of the
femoral artery. We demonstrated the inhibiting effect
of these agents upon smooth muscle cells through the
activation of Ca2+-dependent potassium conductance.
The action of 2'-5'-A3 may be eliminated by the use of
high-conductance calcium-activated potassium channel
blockers (BKCa) or by a protein kinase A inhibitor. The
inhibition of vasodilating action of 2'-5'-triadenylate by
cAMP-dependent protein kinase may imply that 2'-5'-A3
can inhibit vasoconstriction through activation of cAMP-
dependent protein kinase by 2'-5'- triadenylate. In addi-
tion, cAMP-dependent protein kinase can phosphory-
late BKCa channels, thus, activating them. It can also act
upon other proteins involved in the contraction-rela-
xation of smooth muscle cells [46].
Subsequently, we investigated the action of 2'-5'-A3
on intracellular Ca2+ metabolism on a model of pituitary
tumor cells (GH3). The membrane of GH3 cells is known
to contain two types of channels which are activated by
low (LVA) and high voltage (HVA). The activity of the-
se voltage-gated channels depends on phosphorylation
of membrane proteins involved in ion transportation, in-
cluding transportation of the calcium ions. Phospho-
rylation is catalyzed by protein kinases; therefore, the
changes of current flux through voltage-gated calcium
channels may be used as a marker of degree of phos-
phorylation of membrane-binded proteins and a marker
of the overall intracellular function.
We studied the action of core 2'-5'-A3, 2'-5'-A3epo-
xy and 3'-5'-A3 upon phosphorylation-dependent Ca2+
channels in GH3 cells. Experiments on these cells re-
vealed an increase in the amplitude of phosphorylation-
dependent Ca2+ L-currents and prolongation of progres-
sive decline of the amplitude of these currents. Core 2'-
5'-A3 and their analogs exhibit similar action upon in-
crease and decrease of Ca2+ currents of HVA, and thus,
possibly, on the increase of the intercellular phospho-
rylation level [47].
L-carrents flowing through the Ca2+ channels are
known to be interrelated with the activation of protein
kinases A and C. We performed a molecular modeling
of interaction between 2'-5'-A3 (and their modified ana-
logs) and protein kinase C. 2'-5'-A3 and their analogs
were shown to get binded with protein kinase C within
271
2'-5'-OLIGOADENYLATES AS A «TOOL» OF INNATE IMMUNITY
a katalytic center on the enzyme. 2'-5'-A3epoxy was cha-
racterized by the most effective binding and by the most
compact location within the active protein kinase center.
Binding depends on the number of adenosine chains, the
trimmers being the most favorable for binding. 2'-5'-A3
and protein kinase C interaction is supposed to cause sti-
mulation of protein kinase C interaction with IP3-recep-
tors and further release of Ca2+ ions [48].
Action upon the function of signal proteins. The
obtained results permitted us to suggest the possible me-
chanism of action of core 2'-5'-A3, involving their bin-
ding with cellular signal proteins which, in its turn, re-
sults in significant alteration of conformation of these
proteins and may significantly modulate their activity,
either increasing or decreasing it. First and foremost, this
is pertinent to protein kinases and Ca2+-binding proteins.
We found direct evidence that core 2'-5'-A3 and their
analogs modulate the activity of eight different protein
kinases either stimulating or inhibiting proteinase acti-
vity. The most prominent inhibitory activity is exhibi-
ted by 2'-5'-A3-amino analog, containing the 8-amino-
adenosine compound. The titrimetric curves of titration
of protein kinase Aurora with 2'-5'-A3 and 2'-5'-A3epo-
xy were not linear having V- or W-shaped [49]. We
suggest that interactions with 2'-5'-A3 and their analogs
may occur beyond the fuctionally active sites of protein
kinases, leading to the changes of protein conformation
and thus, to the changes of enzyme activity. The fin-
dings demonstrating the capacity of 2'-5'-A3 to not only
inhibit, but also to stimulate protein kinase activity, fa-
vour this suggestion. That is why it is possible that 2'-
5'-A3 and its analogs modulate the activity of protein ki-
nases by causing their conformational changes.
Various extracellular and intracellular signals cause
the increase of cytoplasmatic ionized Ca2+ levels. Cal-
cium, in its turn, actively interacts with calcium-binding
proteins, in particular with calmodulin. Calmodulin is a
small protein with a molecular weight of 18.000 Da.
Considering the results discussed above, we suggested
that 2'-5'-A3 get binded with calmodulin thus influen-
cing its conformation and functional activity. The use of
pure calmodulin demonstrated that 2'-5'-A3 and 2'-5'-A3
epoxy significantly increase the degree of binding of
labeled 45Ca2+ with this protein. 2'-5'-A3, 2'-5'-A3epoxy
and 2'-5'-A3cord increase three-fold the affinity of cal-
modulin to calcium ions. 2'-5'-A3cord significantly in-
creased the maximal binding capacity of Ca2+ with cal-
modulin. Therefore, calmodulin represents a molecular
target for 2'-5'-A3 and its analogs, which by increasing
the affinity of this protein to Ca2+ ions, activate the pro-
cess of this cation binding [50].
We assume that other target proteins of core 2'-5'-
A3 are present in cells. The search for these proteins and
the study of their interactions with 2'-5'-oligoadenyla-
tes would permit to establish some fundamental mecha-
nisms of regulation of cellular processes as well as to de-
velop new therapeutic agents. 2'-5'-A3 agents were shown
to decrease effectively the fluorescence of albumin,
and to a lesser extent that of IFN. This is a proof of inter-
action and binding of oligoadenylates with these pro-
teins. Their interaction in most cases occurs in the pre-
sence of tyrosine compounds, while the role of trypto-
phan is usually less significant. These agents practical-
ly did not affect the emission of immunoglobulin G.
The 2-5-A3-amino analog appeared to be the most effec-
tive ligand of INFs, with tryptophan playing a key role
in this interaction [51, 52].
We applied the method of low temperature autolu-
minescence for spectral testing of albumin binding with
oligonucleotides. Due to structured spectra of autophos-
phorescence at low temperatures, the binding of human
albumin with 2'-5'-A3 molecules was confirmed [53, 54].
Many works dedicated to the study of biological ac-
tivity of 2'-5'-A3 demonstrated that the mechanism of
their antiviral action is related to their capacity to act
upon the proteins of 2'-5'-oligoadenylatsynthetase/en-
doribonuclease L (2'-5'-OAS/RNase L) system, which,
in its turn, leads to the destruction of viral RNA. How-
ever, the main role in the antiviral defence belongs to
IFNs which not only induce the expression of genes in-
volved in the antiviral cellular mechanisms, but also, ac-
cording to the recent studies of Silverman, can get self-
activated by oligonucleotide products of viral RNA
cleavage produced by RNase L [55].
From here a question is arises regarding the capaci-
ty of core 2'-5'-A3 and 3'-5'A3 to bind directly with IFN,
and thus to influence its functions. The study of pro-
tein-oligonucleotide interactions was performed with
the use of mass-spectrometry (MALDI-TOF). 3'-5'-A3,
2'-5'-A3 and its epoxy analog were demonstrated to be
capable of binding with �-IFN. Core 2'-5'-A3 and 3'-5'-
A3 have multiple interactions with �-IFN resulting in
272
TKACHUK Z. Yu.
formation of stable complexes. They do not bind with
insulin which is not a component of a 2'-5'-OAS/RNase
system [56, 57].
The conformational changes in IFN, calmodulin and
S100A1 were studied with the use of Fourier transform
infrared spectroscopy (FTIR). Changes of absorption
spectrum were found in all complexes of the studied
proteins and 2'-5'-A3, corresponding to the amide I and
amide II regions which are known as indicators of the
state of the secondary structure of a protein globule.
Moreover, the changes were revealed in the 1200–1100
cm–1 region, indicating the contribution of 2'-5'-A3 car-
bohydrate component to the interaction with target pro-
teins. The above data serve as a direct proof of binding
of the studied proteins with 2'-5'-A3 and their influence
on their conformation [58].
With the use of a circular dichroism spectroscopy
(CD-spectroscopy) the changes of secondary structures
of the protein S100A1 were studied. The protein apo
(without Ca2+ ions) and holo (with Ca2+ ions) forms we-
re investigated. S100A1 exists as a homodyne which is
expressed in the heart tissue where it plays an important
regulatory role in the Ca2+ homeostasis. In our study,
with the use of CD and fluorescent spectroscopy we
have established that 2'-5'-A3 influences the structure
and function of S100A1. The CD spectra have demonst-
rated that 2'-5'-A3 causes small conformational changes
in apo-S100A1 structures. The structural changes are
predominantly localized in the linker region and/or in
the C-terminal region of the spiral IV. The analysis of
the binding constant shows that 2'-5'-A3, probably binds
relatively weakly with the human S100A1. Neverthe-
less, addition of 2'-5'-A3 to the apo-form of S100A1 sig-
nificantly increases the Ca2+-binding constants. Interes-
tingly, this effect is more noticeable in the presence of
epoxy 2'-5'-A3 derivative. Therefore, our studies show
that binding of 2'-5'-A3 causes small structural changes
in S100A1 leading to the increase of affinity of Ca2+ to the
protein. They may be considered as a proof of «soft
influence» during 2'-5'-A3 and S100A1 interaction.
Summarizing the data from literature and the results
of our studies, we can state that the cores of 2'-5'-oligo-
adenylates and their analogs possess a significantly wi-
der spectrum of biological activity than predicted within
the limits of the traditional «interferon» hypothesis.
They exhibit immunomodulating action as well as they
act as very effective immunosupressants, thus being able
to regulate reactions of transplanted organ or tissue re-
jection. Oligoadenylates possess a wide spectrum of ac-
tivity against both DNA- and RNA-containing viruses.
These agents regulate apoptosis and proliferation of
cells, possess an antitumor activity and influence the
contraction of smooth muscle cells. It is clear that such
multidirectional activity should be based on characteris-
tic molecular mechanisms allowing them to participate
in such a wide spectrum of biological effects. All the
above-named biological effects of these substances seem
to fit into the system of innate defense, including cAMP,
Ca2+-binding proteins, protein kinases, interferons and
cytokines, 2'-5'-oligoadenylate synthetase and RNase
L, restrictases, nucleases, and other proteins.
We attempted to study these proteins, in part, and to
find the common characteristics permitting these sub-
stances to perform their regulatory functions. With the
use of various techniques we have established that oli-
goadenylates can bind with signal proteins with a asso-
ciation constant of about 10–5–10–6 M. This leads to con-
formational changes of the signal proteins and hence to
the changes of their affinity and modulation of the acti-
vity. These are the principal properties of oligoadenyla-
tes with regard to signal proteins.
Considering the established properties of oligoade-
nylates, we proposed a hypothesis explaining the me-
chanism of their antiviral action. According to this hy-
pothesis, the cores of 2'-5'-oligoadenylates, formed as a
result of ppp2'-5'-A3 and RNase L interaction, change
the structure of viral DNAs and RNAs in a way that they
become exposed to cleavage by cellular nucleases, phos-
phodiesterases, and phosphatases. They can also cause
conformational changes of viral and cellular receptors,
inhibiting virus entry and exit from cells. Simultaneous-
ly, oligoadenylates by changing the conformation of the
signaling molecules, may influence proliferation of the
immune cells as well as migration of bone marrow stem
cells. Acting upon the expression of genes of cellular
defense, and, first of all, those of cytokines, they may re-
gulate the balance between inflammatory and antiin-
flammatory processes.
The commercialization of synthetic 2'-5'-A3 analogs
in pharmaceutical industry was weighed down by ex-
tremely high cost of their production. Therefore, based
on the hypothesis suggested in 2000, we separated from
273
2'-5'-OLIGOADENYLATES AS A «TOOL» OF INNATE IMMUNITY
yeasts a relatively cheap substance consisting of natu-
ral oligonucleotides. This substance was the basis for
development and introduction into medical practice of
a medication Nucleinat, possessing immunomodula-
ting and antiinflammatory properties [59, 60]. This me-
dication appears to be especially effective in the chro-
nic inflammatory processes accompanied by immuno-
deficiency. In 2010, industrial processing of this sub-
stance resulted in development of Nuclex, a broad-
spectrum antiviral agent possessing the antiviral pro-
perties of 2'-5'-A3 analogs, and active against various
RNA- and DNA-containing viruses [61]. Further stu-
dies of the role of oligoadenylates in the regulation of
signaling pathways and gene expression of the innate
immunity will permit to precise the spectrum of natural
therapeutic oligonucleotides and their potential for re-
gulation of the innate antitumor defense. This appoach
gives hope for developing effective antitumor agents
the action of which would be aimed at the regulation of
the host antitumor defense system.
Ç. Þ. Òêà÷óê
2'-5'-îë³ãîàäåí³ëàòè ÿê «³íñòðóìåíò» óðîäæåíîãî ³ìóí³òåòó
Ðåçþìå
³äîìî, ùî «êîðè» 2'-5'-îë³ãîàäåí³ëàò³â òà ¿õí³õ àíàëîãè âî-
ëîä³þòü çíà÷íî øèðøîþ á³îëîã³÷íîþ àêòèâí³ñòþ, í³æ öå ìîæíà
ïåðåäáà÷èòè â ðàìêàõ òðàäèö³éíî¿ «³íòåðôåðîíîâî¿» ã³ïîòåçè.
Âîíè ïðîÿâëÿþòü ³ìóíîìîäóëþþ÷ó ä³þ ³ º åôåêòèâíèìè ³ìóíîñóï-
ðåñîðàìè ïðè òðàíñïëàíòàö³¿ îðãàí³â ³ òêàíèí. Îë³ãîàäåí³ëàòàì
ïðèòàìàííà ïðîòèâ³ðóñíà àêòèâí³ñòþ ñòîñîâíî øèðîêîãî ñïåê-
òðà ÿê ÄÍÊ-, òàê ³ ÐÍÊ-âì³ñíèõ â³ðóñ³â. Ö³ ïðåïàðàòè ðåãóëþ-
þòü àïîïòîç ³ ïðîë³ôåðàö³þ êë³òèí òà âîëîä³þòü ïðîòèïóõëèí-
íîþ àêòèâí³ñòþ. Òàêà ïîë³âàëåíòíà àêòèâí³ñòü îë³ãîàäåí³ëàò³â
áàçóºòüñÿ íà ìîæëèâîñò³ çâ’ÿçóâàòèñÿ ç ñèãíàëüíèìè á³ëêàìè,
ùî ïðèçâîäèòü äî çì³íè ¿õíüî¿ êîíôîðìàö³¿ òà ìîäóëÿö³¿ àêòèâ-
íîñò³. Âîíè òàêîæ ìîæóòüïîðóøóâàòè âòîðèííó ñòðóêòóðó
â³ðóñíèõ ÄÍÊ ³ ÐÍÊ ³ ðîáëÿòü ¿õ äîñòóïíèìè äëÿ ðîçùåïëåííÿ
êë³òèííèìè ôåðìåíòàìè. Çàïðîïîíîâàíî ã³ïîòåçó, ÿêà ïîÿñíþº
ìåõàí³çì ïðîòèâ³ðóñíî¿ ä³¿ 2'-5'-îë³ãîàäåí³ëàò³â, à òàêîæ íàâåäå-
íî åêñïåðèìåíòàëüí³ äàí³ íà ¿¿ êîðèñòü.
Êëþ÷îâ³ ñëîâà: 2'-5'-îë³ãîàäåí³ëàòè, 2'-5'-îë³ãîàäåí³ëàòñèíòå-
òàçà, �-³íòåðôåðîí, ïðîòå¿íê³íàçè, Ñà
2+
-çâ’ÿçóâàëüí³ á³ëêè, ÐÍÊ-,
ÄÍÊ-â³ðóñè.
Ç. Þ. Òêà÷óê
2',5'-îëèãîàäåíèëàòû êàê «èíñòðóìåíò» âðîæäåííîãî èììóíèòåòà
Ðåçþìå
Èçâåñòíî, ÷òî «êîðû» 2'-5'-îëèãîàäåíèëàòîâ è èõ àíàëîãè îáëà-
äàþò áîëåå øèðîêîé áèîëîãè÷åñêîé àêòèâíîñòüþ, ÷åì ýòî ìîæ-
íî ïðåäïîëîæèòü â ðàìêàõ òðàäèöèîííîé «èíòåðôåðîíîâîé» ãè-
ïîòåçû. Îíè ïðîÿâëÿþò èììóíîìîäóëèðóþùåå äåéñòâèå è ÿâëÿ-
þòñÿ ýôôåêòèâíûìè èììóíîñóïðåññîðàìè ïðè òðàíñïëàíòàöèè
îðãàíîâ è òêàíåé. Îëèãîàäåíèëàòàì ïðèñóùà àíòèâèðóñíàÿ àê-
òèâíîñòü îòíîñèòåëüíî øèðîêîãî ñïåêòðà êàê ÄÍÊ-, òàê è ÐÍÊ-
ñîäåðæàùèõ âèðóñîâ. Ýòè ïðåïàðàòû ðåãóëèðóþò àïîïòîç è ïðî-
ëèôåðàöèþ êëåòîê è îáëàäàþò ïðîòèâîîïóõîëåâîé àêòèâíîñòüþ.
Òàêàÿ ïîëèâàëåíòíàÿ àêòèâíîñòü îëèãîàäåíèëàòîâ áàçèðóåòñÿ
íà âîçìîæíîñòè ñâÿçûâàòüñÿ ñ ñèãíàëüíûìè áåëêàìè, ÷òî ïðè-
âîäèò ê èçìåíåíèþ èõ êîíôîðìàöèè è ìîäóëÿöèè àêòèâíîñòè.
Îíè òàêæå ìîãóò íàðóøàòü âòîðè÷íóþ ñòðóêòóðó âèðóñíûõ ÄÍÊ
è ÐÍÊ è äåëàòü èõ äîñòóïíûìè äëÿ ðàñùåïëåíèÿ êëåòî÷íûìè
ôåðìåíòàìè. Ïðåäëîæåíà ãèïîòåçà, îáúÿñíÿþùàÿ ìåõàíèçì ïðî-
òèâîâèðóñíîãî äåéñòâèÿ 2'-5'-îëèãîàäåíèëàòîâ, è ïðèâåäåíû ýêñ-
ïåðèìåíòàëüíûå äàííûå â åå ïîëüçó.
Êëþ÷åâûå ñëîâà: 2'-5'-îëèãîàäåíèëàòû, 2'-5'-îëèãîàäåíèëàò-
ñèíòåòàçà, �-èíòåðôåðîí, ïðîòåèíêèíàçû, Ñà
+2
-ñâÿçûâàþùèå
áåëêè, ÐÍÊ-, ÄÍÊ-ñîäåðæàùèå âèðóñû.
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Received 30.12.12
|
| id | nasplib_isofts_kiev_ua-123456789-152604 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 0233-7657 |
| language | English |
| last_indexed | 2025-11-28T20:14:57Z |
| publishDate | 2013 |
| publisher | Інститут молекулярної біології і генетики НАН України |
| record_format | dspace |
| spelling | Tkachuk, Z.Yu. 2019-06-12T13:08:30Z 2019-06-12T13:08:30Z 2013 2'-5'-Oligoadenylates as a «tool» of innate immunity / Z.Yu. Tkachuk // Вiopolymers and Cell. — 2013. — Т. 29, №. 4. — С. 266-276. — Бібліогр.: 61 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000821 https://nasplib.isofts.kiev.ua/handle/123456789/152604 615.281 It is a matter of common knowledge, that «core» 2'-5'-oligoadenylates and their analogues posses broader biological activity than it can be predicted within the traditional «interferon» hypothesis. They exhibit immunomodulatory effects and are effective immunosuppressive agents upon organ and tissue transplantation. Oligoadenylates render antiviral activity against a wide range of viruses both DNA and RNA origin. These drugs regulate apoptosis, cell proliferation and possess antitumor activity. Such polyvalent activity is based on their ability to bind signaling proteins, slightly altering their conformation and modulating their activity. They can also change the secondary structure of both viral DNA and RNA, making them accessible for enzymatic cleavage. The hypothesis forwarded within this review is aimed at making an attempt to explain the mechanism of 2'-5'-oligoadenylates antiviral action. Our recent papers, containing experimental data to support this hypothesis, are discussed in this review. Відомо, що «кори» 2'-5'-олігоаденілатів та їхніх аналоги володіють значно ширшою біологічною активністю, ніж це можна передбачити в рамках традиційної «інтерферонової» гіпотези. Вони проявляють імуномодулюючу дію і є ефективними імуносупресорами при трансплантації органів і тканин. Олігоаденілатам притаманна противірусна активністю стосовно широкого спектра як ДНК-, так і РНК-вмісних вірусів. Ці препарати регулюють апоптоз і проліферацію клітин та володіють протипухлинною активністю. Така полівалентна активність олігоаденілатів базується на можливості зв’язуватися з сигнальними білками, що призводить до зміни їхньої конформації та модуляції активності. Вони також можутьпорушувати вторинну структуру вірусних ДНК і РНК і роблять їх доступними для розщеплення клітинними ферментами. Запропоновано гіпотезу, яка пояснює механізм противірусної дії 2'-5'-олігоаденілатів, а також наведено експериментальні дані на її користь. Известно, что «коры» 2'-5'-олигоаденилатов и их аналоги обладают более широкой биологической активностью, чем это можно предположить в рамках традиционной «интерфероновой» гипотезы. Они проявляют иммуномодулирующее действие и являются эффективными иммуносупрессорами при трансплантации органов и тканей. Олигоаденилатам присуща антивирусная активность относительно широкого спектра как ДНК-, так и РНК- содержащих вирусов. Эти препараты регулируют апоптоз и пролиферацию клеток и обладают противоопухолевой активностью. Такая поливалентная активность олигоаденилатов базируется на возможности связываться с сигнальными белками, что приводит к изменению их конформации и модуляции активности. Они также могут нарушать вторичную структуру вирусных ДНК и РНК и делать их доступными для расщепления клеточными ферментами. Предложена гипотеза, объясняющая механизм противовирусного действия 2'-5'-олигоаденилатов, и приведены экспериментальные данные в ее пользу. en Інститут молекулярної біології і генетики НАН України Вiopolymers and Cell Reviews 2'-5'-Oligoadenylates as a «tool» of innate immunity 2'-5'-олігоаденілати як «інструмент» уродженого імунітету 2',5'-олигоаденилаты как «инструмент» врожденного иммунитета Article published earlier |
| spellingShingle | 2'-5'-Oligoadenylates as a «tool» of innate immunity Tkachuk, Z.Yu. Reviews |
| title | 2'-5'-Oligoadenylates as a «tool» of innate immunity |
| title_alt | 2'-5'-олігоаденілати як «інструмент» уродженого імунітету 2',5'-олигоаденилаты как «инструмент» врожденного иммунитета |
| title_full | 2'-5'-Oligoadenylates as a «tool» of innate immunity |
| title_fullStr | 2'-5'-Oligoadenylates as a «tool» of innate immunity |
| title_full_unstemmed | 2'-5'-Oligoadenylates as a «tool» of innate immunity |
| title_short | 2'-5'-Oligoadenylates as a «tool» of innate immunity |
| title_sort | 2'-5'-oligoadenylates as a «tool» of innate immunity |
| topic | Reviews |
| topic_facet | Reviews |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/152604 |
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