104
According to the chemical nature, the pol inhibitors can be divided into two
large groups—substrate analogs (nucleoside/nucleotide/dNTP compounds) and all
other compounds
2
. This division reflects the special role played by nucleotides in
replicative/repair processes. Due to the chemical similarity to natural DNA polymerase substrate, practically any nucleoside/nucleotide analogs are able to bind
with active site, thus competing with the natural substrates of DNA polymerases.
At first glance, selectivity of these inhibitors is not out of the question. However,
one should mention that amino acid compositions of dNTP-binding sites are distinct
in different DNA pol families and, thus, affinity of various nucleotide inhibitors to
them also can be substantially different.
There are at least three types of nucleoside inhibitors’ behavior at the DNA polymerase active site:
• the nucleoside analog incorporates in the growing DNA chain and terminates
the next DNA synthesis due to the lack or modification of the 3′-OH group in
its composition. Strictly speaking, such compound does not influence the DNA
polymerase activity itself, but prevents the addition of the next nucleotide only;
• the nucleoside analog binds at the active center of DNA polymerase, but does not
incorporate in the DNA chain;
• the nucleoside analog incorporates in the growing DNA chain and (possibly)
deforms the spatial geometry of the active center, which results in a slowdown of
the further inclusion of natural nucleotides.
The inhibitors of DNA polymerases have been found among dNTP derivates modified in the base (2-substituted dATP and N
2
-substituted dGTP analogs, derivatives
with altered base-pairing specificity), derivates modified in the sugar (arabinonucleotides, 2′,3′-dideoxynucleotides, acyclonucleotides) and derivates modified in
the triphosphate group (for example, phosphorothioates of dATP) [31–33].
Among nucleotide inhibitors one should specially mention acyclic nucleoside
phosphonates, in particular, (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] nucleosides (HPMP) [34, 35]. These compounds exhibit activity with respect to a wide
spectrum of viral and eukaryotic DNA polymerases—herpes simplex virus 1 (HSV1) DNA polymerase [36], human cytomegalovirus HCMV DNA polymerase [37,
38], vaccinia virus DNA polymerase [39, 40], human DNA polymerases α, δ, and
ε [41] as well as reverse transcriptases [42]. Several antiviral drugs with a wide
spectrum of targets are developed on the basis of acyclic nucleoside phosphonates.
Among them one can mention cidofovir (commercial name vistide
®
) (Fig. 4.3) that
is used against polyoma-, papilloma-, adeno-, herpes-, irido- and poxviruses [34,
43, 44], tenofovir ( viread
®
) acting on hepata- and retoviruses [34, 43], adefovir
( hepsera
®
) (Fig. 4.4), which is effective against all above mentioned groups of viruses [34, 43]. A feature of the HPMP interaction with DNA replicative machine is
that they are not simple terminators of the DNA chain growth. These compounds
can be incorporated into DNA and this, in principle, permits the continuation of
DNA synthesis, but it becomes significantly slower [35].
2
Some researchers [31] consider the pyrophosphate analogs as a separate inhibitor group (product
analogs’ group).
A. Yu. Nyporko
According to the chemical nature, the pol inhibitors can be divided into two
large groups—substrate analogs (nucleoside/nucleotide/dNTP compounds) and all
other compounds
2
. This division reflects the special role played by nucleotides in
replicative/repair processes. Due to the chemical similarity to natural DNA polymerase substrate, practically any nucleoside/nucleotide analogs are able to bind
with active site, thus competing with the natural substrates of DNA polymerases.
At first glance, selectivity of these inhibitors is not out of the question. However,
one should mention that amino acid compositions of dNTP-binding sites are distinct
in different DNA pol families and, thus, affinity of various nucleotide inhibitors to
them also can be substantially different.
There are at least three types of nucleoside inhibitors’ behavior at the DNA polymerase active site:
• the nucleoside analog incorporates in the growing DNA chain and terminates
the next DNA synthesis due to the lack or modification of the 3′-OH group in
its composition. Strictly speaking, such compound does not influence the DNA
polymerase activity itself, but prevents the addition of the next nucleotide only;
• the nucleoside analog binds at the active center of DNA polymerase, but does not
incorporate in the DNA chain;
• the nucleoside analog incorporates in the growing DNA chain and (possibly)
deforms the spatial geometry of the active center, which results in a slowdown of
the further inclusion of natural nucleotides.
The inhibitors of DNA polymerases have been found among dNTP derivates modified in the base (2-substituted dATP and N
2
-substituted dGTP analogs, derivatives
with altered base-pairing specificity), derivates modified in the sugar (arabinonucleotides, 2′,3′-dideoxynucleotides, acyclonucleotides) and derivates modified in
the triphosphate group (for example, phosphorothioates of dATP) [31–33].
Among nucleotide inhibitors one should specially mention acyclic nucleoside
phosphonates, in particular, (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] nucleosides (HPMP) [34, 35]. These compounds exhibit activity with respect to a wide
spectrum of viral and eukaryotic DNA polymerases—herpes simplex virus 1 (HSV1) DNA polymerase [36], human cytomegalovirus HCMV DNA polymerase [37,
38], vaccinia virus DNA polymerase [39, 40], human DNA polymerases α, δ, and
ε [41] as well as reverse transcriptases [42]. Several antiviral drugs with a wide
spectrum of targets are developed on the basis of acyclic nucleoside phosphonates.
Among them one can mention cidofovir (commercial name vistide
®
) (Fig. 4.3) that
is used against polyoma-, papilloma-, adeno-, herpes-, irido- and poxviruses [34,
43, 44], tenofovir ( viread
®
) acting on hepata- and retoviruses [34, 43], adefovir
( hepsera
®
) (Fig. 4.4), which is effective against all above mentioned groups of viruses [34, 43]. A feature of the HPMP interaction with DNA replicative machine is
that they are not simple terminators of the DNA chain growth. These compounds
can be incorporated into DNA and this, in principle, permits the continuation of
DNA synthesis, but it becomes significantly slower [35].
2
Some researchers [31] consider the pyrophosphate analogs as a separate inhibitor group (product
analogs’ group).
A. Yu. Nyporko