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M. Ilchenko and I. Dubey
undergo a large number of cell divisions. Normally telomeric DNA is shortened by
50–200 nucleotides upon each cellular division that may control the proliferative
capacity of normal somatic cells. However, this does not occur in tumor cells due
to high activity of telomerase, an enzyme which is responsible for maintaining the
telomere length and synthesizes the lost telomeric sequences by adding telomeric
repeats (5’-TTAGGG-3’ sequence in humans), that leads to uncontrolled proliferation. Inhibition of telomerase activity induces senescence in cancer cells followed
by their death. In contrast, normal somatic cells are devoid of telomerase activity,
so high level of enzyme expression is directly associated with cancer. Indeed, increased telomerase activity was detected in 85–90 % of human tumors [1, 3]. As a
result, telomerase system is now considered a promising biological target for novel
anticancer drugs.
Telomerase is a multicomponent highly specialized enzyme responsible for the
synthesis of telomeres. Its catalytic subunit (TERT, telomerase reverse transcriptase) utilizes the RNA component of the enzyme (TR) as a template to synthesizes
telomeric DNA repeats. A number of strategies for telomerase inhibition by lowmolecular drugs have been proposed. They include the application of nucleoside
and non-nucleoside reverse transcriptase inhibitors, antisense oligonucleotides and
their analogues against TR RNA, ribozymes and siRNA directed against TR and
TERT components of the enzyme, etc. [5–9]. These approaches are rather traditional for the inhibition of enzymes of nucleic acids biosynthesis. Totally different
approach is based on the presence of unique structural motifs in telomeric DNA
called G-quadruplexes (G4).
Certain guanine-rich DNA sequences readily fold into the four-stranded structures formed by stacked arrays of guanine quartets (or tetrads) – square planar arrangements of four guanine bases connected by Hoogsteen-type hydrogen bonds
(Fig. 6.1).
These stable higher-order DNA arrangements were shown to play a crucial biological role in a living cell. DNA sequences able to adopt quadruplex structures are
prevalent in telomeres as telomeric repeats, although they have been also found in
a number of gene promoter regions, first of all in proto-oncogenes, like c-myc, c-kit
or k-ras, that can be also targeted by drugs [10–15]. RNA sequences can also form
quadruplex structures as recent finding demonstrated that telomere DNA is transcribed into telomeric repeat-containing RNA [11, 16–18].
Perhaps the formation and dissociation of quadruplex structures in nucleic acids
is one of the universal ways of the regulation of gene expression in vivo. So the
development of specific quadruplex ligands, besides the development of anticancer compounds, would allow controlling many fundamental biological processes.
Therefore, quadruplex nucleic acids are an important new target for drug design,
and there is growing interest in the development of small molecules targeting these
structures with high affinity and selectivity.
M. Ilchenko and I. Dubey
undergo a large number of cell divisions. Normally telomeric DNA is shortened by
50–200 nucleotides upon each cellular division that may control the proliferative
capacity of normal somatic cells. However, this does not occur in tumor cells due
to high activity of telomerase, an enzyme which is responsible for maintaining the
telomere length and synthesizes the lost telomeric sequences by adding telomeric
repeats (5’-TTAGGG-3’ sequence in humans), that leads to uncontrolled proliferation. Inhibition of telomerase activity induces senescence in cancer cells followed
by their death. In contrast, normal somatic cells are devoid of telomerase activity,
so high level of enzyme expression is directly associated with cancer. Indeed, increased telomerase activity was detected in 85–90 % of human tumors [1, 3]. As a
result, telomerase system is now considered a promising biological target for novel
anticancer drugs.
Telomerase is a multicomponent highly specialized enzyme responsible for the
synthesis of telomeres. Its catalytic subunit (TERT, telomerase reverse transcriptase) utilizes the RNA component of the enzyme (TR) as a template to synthesizes
telomeric DNA repeats. A number of strategies for telomerase inhibition by lowmolecular drugs have been proposed. They include the application of nucleoside
and non-nucleoside reverse transcriptase inhibitors, antisense oligonucleotides and
their analogues against TR RNA, ribozymes and siRNA directed against TR and
TERT components of the enzyme, etc. [5–9]. These approaches are rather traditional for the inhibition of enzymes of nucleic acids biosynthesis. Totally different
approach is based on the presence of unique structural motifs in telomeric DNA
called G-quadruplexes (G4).
Certain guanine-rich DNA sequences readily fold into the four-stranded structures formed by stacked arrays of guanine quartets (or tetrads) – square planar arrangements of four guanine bases connected by Hoogsteen-type hydrogen bonds
(Fig. 6.1).
These stable higher-order DNA arrangements were shown to play a crucial biological role in a living cell. DNA sequences able to adopt quadruplex structures are
prevalent in telomeres as telomeric repeats, although they have been also found in
a number of gene promoter regions, first of all in proto-oncogenes, like c-myc, c-kit
or k-ras, that can be also targeted by drugs [10–15]. RNA sequences can also form
quadruplex structures as recent finding demonstrated that telomere DNA is transcribed into telomeric repeat-containing RNA [11, 16–18].
Perhaps the formation and dissociation of quadruplex structures in nucleic acids
is one of the universal ways of the regulation of gene expression in vivo. So the
development of specific quadruplex ligands, besides the development of anticancer compounds, would allow controlling many fundamental biological processes.
Therefore, quadruplex nucleic acids are an important new target for drug design,
and there is growing interest in the development of small molecules targeting these
structures with high affinity and selectivity.