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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5542_Библиотеки_им_академика_М_И_Перельмана.pdf
Cisplatin Derivatives as Antiviral Agents
37
substance. This continual release of bioactive medications is essential for
cell-cycle-specific therapeutics and also drug resistance reduction
Nevertheless, all antivirals suffer from the effects of target specificit .
Viruses, for the most part, replicate the viral genome and make new virus
particles using cellular machinery. In an attempt to attack viral replication,
uninfected cells’ biological activities are also adversely impacted. A few of
these side effects can be avoided using polymeric medicines
There has been an investigation of a variety of metal-containing
polymers as possible antiviral drugs, with a focus on platinum and organotincontaining polymers. Polymeric medications have several potential benefits
over monomeric or small molecule therapies.
Researchers have suggested that at least some cancers have a viral
relationship. Thus, we have begun testing polymers that show good
anticancer activity against a variety of viruses.
Experts suspect that at least some malignancies are linked to viruses.
As a result, scientists recently started to implement testing polymers with
anticancer activity against a number of viruses. Researchers recently
examined a variety of organotin products made from well-known antibacterial
medicines, including ciprofloxacin, ampicillin (Figure 2.1.), and norfloxacin
(Figure 2.2.). All of these drugs showed antiviral activity against a variety
of viruses, including reovirus ST3, vaccinia virus, herpes simplex virus
(HSV-1), and varicella zoster virus (VZV). At doses of around 2 mg/ml,
the organotin polymers of norfloxacin and ampicillin inhibited virus growth
completely, but neither norfloxacin nor ampicillin inhibited virus growth.
Organotin derivatives of the well-known antiviral medication acyclovir
were also assessed. Again, the organotin polymers inhibited the viruses at
lower concentrations than acyclovir alone.
Figure 2.1. Dibutyltin-ampicillin polymer.
Introduction to the Study of Macromolecules
38
Figure 2.2. Dibutyltin-norfloxacin polyme .
As a result, the combination of recognized medicines with organotin
moieties inside polymers appears to be more potent antiviral agents than
either of the reactants alone.
The interest in these organotin-containing polymers stems from the fact
that they are strong anticancer drugs capable of suppressing cancer cell
proliferation at doses comparable to or lower than cisplatin. Furthermore,
these organotin polymers are far less hazardous than the most commonly
used anticancer medication, cisplatin.
For over 30 years, researchers have been researching a variety of
polymeric cisplatin derivatives as anticancer medicines. Once more,
scientists have produced polymeric medicines that limit cancer cell growth
at concentrations comparable to cisplatin, and these compounds are
significantly less hazardous. Some of these polymeric cisplatin derivatives
have also been studied as antiviral agents.
2.2. INHIBITION
The vast majority of viruses are RNA viruses. It is not unexpected that they
are also responsible for the vast majority of human ailments. Some of the
most well-known illnesses caused by RNA viruses are as follows:
• Common Cold
• Poliomyelitis
• Hepatitis
• Encephalitis
• Yellow Fever
• Rubella
Cisplatin Derivatives as Antiviral Agents
39
• Influenz
• Measles
• Mumps
• Various Hemorrhagic Fevers
2.2.1. Features of an Ideal Antiviral Drug
An ideal antiviral medicine would have the following characteristics:
efficient suppression of a critical viral function, a mechanism to prevent the
development of drug-resistant viruses, broad-spectrum effectiveness against
RNA and DNA viruses, and no deleterious influence on host cell activities.
2.2.2. Strategies for Antiviral Therapy
Many antivirals aim for one of five main viral procedures:
1. virus attachment to the host cell,
2. virus penetration and/or uncoating to start releasing the viral
nucleic acid into the host cell,
3. viral genome replication,
4. viral gene expression to start producing viral proteins, and
5. virus structure assembly and maturation and release of progeny
virions with or without host cell lysis.
2.2.3. Attachment
Virus attachment can be prevented in two ways, which are discussed further
below.
1) Viral attachment protein (VAP) mimicking agents can be
introduced into the infected host. These VAPs subsequently
connect to the cellular receptor and prevent the virus from binding.
Anti-idiotypic antibodies that imitate the VAP can be generated.
When these antibodies are delivered to the host, they attach to
the cellular receptors that infectious viruses would typically have
access to.
This “blocks” the viral receptor on the cell, preventing the virus from
adhering and infecting it. Natural ligands of the viral receptor can be used to
bind the receptor and prevent the virus from using it. Vaccinia virus and the
epidermal growth factor (EGF) receptor are two examples of this.
Introduction to the Study of Macromolecules
40
The fourth option is to utilize synthetic ligands that are similar to the
VAP’s receptor-binding domain. These peptides would attach to a cell
receptor and inhibit the receptor from binding to the VAP, so preventing
infectious disease.
2) Agents that operate by binding the VAP and imitating the viral
receptor on the host cell. Antibodies against the VAP, which
are spontaneously created in response to most viruses, bind the
VAP and block it from interacting with host cell receptors. Antiidiotypic antibodies, which imitate the cell receptor or external
receptors utilized by HIV, can be generated.
When these antibodies are injected into the host, they act as “binding
targets” for the virus, but unlike the cells that typically produce these
receptors, they cannot be infected or promote viral reproduction. Furthermore,
synthetic receptor mimics can be created to bind virus before it has a chance
to contact cell receptors. The use of sialic acid derivatives to bind influenza
virus is one example of this strategy.
2.2.4. Penetration and Uncoating
Several viruses’ molecular mechanisms have been challenging to investigate,
making it difficult to particularly target certain phases of the viral life cycle.
Uncoating is primarily mediated by cellular enzymes, but it is frequently
modified by one or more viral proteins, as is penetration.
Pleconaril is an anti-picorna virus agent with a broad spectrum of
activity. It is a tiny cyclic medication that binds to the virus’s capsid pore.
As a result, it prevents the viral particle from attaching and uncoating.
Amantadine (Figure 2.3.) and rimantadine (Figure 2.4.) are both antiviral
drugs that work against influenza A viruses. The mechanism of action of
these closely related drugs is complicated and unknown, however, they are
thought to disrupt cellular membrane ion channels. Both medications work
by targeting the influenza a matrix protein (M2). Drug-treated cells are often
unable to reduce the pH of the endosomal compartment (a function typically
regulated by the M2 gene product), a step required to cause conformational
changes in the HA protein to allow membrane fusion.
2.2.5. Genome Replication
Most viruses have developed their own enzymatic methods to redirect
cellular energy to viral genome replication. There are frequently enough
Cisplatin Derivatives as Antiviral Agents
41
variations between viral and cellular polymerases to give a target for an
antiviral medication while causing no harm to the unaffected agents. This
method produced the vast majority of antiviral medicines now in use.
The majority of these medications work as polymerase substrates, or as
nucleoside/nucleotide analogs.
The toxicity of these medications varies greatly, from those that are
well tolerated, such as acyclovir, to others that are extremely toxic, such as
IdU/TFT and AZT. The pharmacokinetics of these nucleoside analogues is
problematic, as they often have short serum half-lives of 1 to 4 hours.
Nucleoside analogues are pro-drugs, which means they must be
phosphorylated before they can be activated. Acyclovir (Figure 2.5.)
is phosphorylated 200 times faster by the herpes simplex virus (HSV)
thymidine kinase than by cellular enzymes. Gancyclovir (Figure 2.5.) is 10
times more potent than acyclovir against cytomegalovirus (CMV) because it
is selectively phosphorylated by a CMV-encoded enzyme not seen in HSV.
Figures 2.6. – 2.14. show further nucleoside analogs generated from
Acyclovir and Gancyclovir that are active against herpesviruses. Figures
2.15. – 2.17. demonstrate more nucleoside analogues with anti-HIV activity.
Figure 2.3. Amantadine.
Figure 2.4. Rimantadine.
Introduction to the Study of Macromolecules
42
Figure 2.5. Acyclovir.
2.2.6. Gene Expression
Several viruses rely extensively on cellular machinery for viral genome
transcription, mRNA splicing, translation, and protein trafficking. Unlike
genome replication, distinctively viral proteins are not engaged in these
activities, and none have been used as antiviral therapeutic targets yet.
Assembly, Maturation, and Release of Progeny Virus
The mechanisms of viral assembly, maturation, and release of progeny
virus are poorly known for the vast majority of viruses. There are two antiinfluenza medications on the market. These are Relenza in the form of an
aerosol and Tamiflu in the form of a tablet. Tamiflu has antiviral activity
both against influenza A and B viruses. Both of these medications act as
neuraminidase inhibitors, preventing the release of budded viruses from
cells.
Figure 2.6. Gancyclovir.
Cisplatin Derivatives as Antiviral Agents
Figure 2.7. Penciclovir.
43
Figure 2.8. Famciclovir.
Figure 2.9. BVDU.
2.2.7. Additional Antiviral Drugs
If ganciclovir medication is unsuccessful or poorly tolerated, foscarnet
(Figure 2.18.) is a first-line treatment for CMV retinitis and treatment for
CMV colitis. Foscarnet may cure sensitive infections in the brain since it
passes the blood-brain barrier.
Introduction to the Study of Macromolecules
44
Figure 2.10. Brovavir,
Figure 2.11. FIAC.
Figure 2.12. FIAU.
Foscarnet could be used to treat herpes strains that are resistant to
acyclovir therapy. Idoxuridine (IdU) (Figure 2.19.) functions by permanently
Cisplatin Derivatives as Antiviral Agents
45
replacing thymidine in newly generated DNA, resulting in an aberrant,
basically nonfunctional DNA molecule. The medication is very hazardous
to host cells and acts on viral and host cell DNA.
Figure 2.13. (S)-HPMPA.
Figure 2.14. (S)-HPMPC.
Figure 2.15. AZT.
Introduction to the Study of Macromolecules
46
Figure 2.16. ddC.
Figure 2.17. ddI.
Figure 2.18. Foscarnet.
IdU has been restricted to topical treatment of herpes simplex
keratoconjunctivitis due to its severe systemic toxicity. Ribavirin is a
guanosine analogue that prevents many RNA and DNA viruses from
replicating.
Ribavirin (Figure 2.20) is considered to prevent the synthesis of messenger
RNA. Ribavirin inhibits respiratory syncytial virus (RSV), influenza A and
B, HSV-1, HSV-2, and many other viruses in vitro. Vidarabine (adenine
arabinoside, ara-A) (Figure 2.21) inhibits viral DNA synthesis and is used
to treat HSV infections.