Download What are Antiviral agents

• Depending on one's viewpoint, viruses may be regarded
as exceptionally complex aggregations of nonliving
chemicals or as exceptionally simple living microbes.
• Viruses contain a single type of nucleic acid (DNA or RNA)
and a protein coat, sometimes enclosed by an envelope
composed of lipids, proteins, and carbohydrates.
• Viruses are obligatory intracellular parasites. They
multiply by using the host cell's synthesizing machinery to
cause the synthesis of specialized elements that can
transfer the viral nucleic acid to other cells.
• A virion is a complete, fully developed viral particle composed
of nucleic acid surrounded by a coat.
• Helical viruses (for example, Ebola virus) resemble long rods
and their capsids are hollow cylinders surrounding the nucleic
acid.
• Polyhedral viruses (for example, adenovirus) are many-sided.
Usually the capsid is an icosahedron.
• Enveloped viruses are covered by an envelope and are
roughly spherical but highly pleomorphic (for example,
Poxvirus). There are also enveloped helical viruses (for
example, Influenzavirus) and enveloped polyhedral viruses (for
example, Herpesvirus). Pleomorphic: Many-formed. A tumor may be pleomorphic.
• Complex viruses have complex structures. For example, many
bacteriophages have a polyhedral capsid with a helical tail
attached. Bacteriophage: A virus that infects and lyses certain bacteria.
Schematic of Influenza Virus
• Viruses contain either DNA or RNA, never both, and the
nucleic acid may be single- or double-stranded, linear
or circular, or divided into several separate molecules.
• The capsid of some viruses is enclosed by an envelope
consisting of lipids, proteins, and carbohydrates.
• Some envelopes are covered with carbohydrate-protein
complexes called spikes.
• The earliest relationship between cancer and viruses was demonstrated in the early
1900s, when chicken leukemia and chicken sarcoma were transferred to healthy
animals by cell-free filtrates.
• Transformation of Normal Cells into Tumor Cells:
• When activated, oncogenes transform normal cells into cancerous cells.
• Viruses capable of producing tumors are called oncogenic viruses.
• Several DNA viruses and retroviruses are oncogenic.
• The genetic material of oncogenic viruses becomes integrated into the host cell's DNA.
• Transformed cells lose contact inhibition, contain virus-specific antigens (TSTA and T
antigen), exhibit chromosomal abnormalities, and can produce tumors when injected
into susceptible animals.
Anti-influenza Agents
Amantadine · Oseltamivir · Peramivir · Rimantadine · Zanamivir
Anti-herpesvirus agents
Aciclovir · Cidofovir · Docosanol · Famciclovir · Foscarnet ·
Fomivirsen · Ganciclovir · Idoxuridine · Penciclovir · Trifluridine ·
Tromantadine · Valaciclovir · Valganciclovir · Vidarabine
Antiretroviral Agents
NRTIsZidovudine · Didanosine · Stavudine · Zalcitabine ·
Lamivudine · Abacavir · Tenofovir
NNTI’s
Nevirapine · Efavirenz · Delavirdine
PIsSaquinavir · Indinavir · Atazanavir · Ritonavir · Nelfinavir ·
Amprenavir · Lopinavir · Tipranavir
Other antiviral agents
Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin ·
Viramidine
• What are Antiviral agents
• Antiviral agents are used to inhibit production of viruses that cause
disease. Most antiviral agents are only effective while the virus is
replicating.
• It is difficult to find medicines that are selective for the virus as viruses
share most of the metabolic processes of the host cell. However, some
enzymes are only present in viruses and these are potential targets
for antiviral drugs.
• Agents that inhibit the transcription of the viral genome are DNA
polymerase inhibitors and reverse transcriptase inhibitors. Protease
inhibitors inhibit the post-translational events. Other antiviral agents
inhibit the virus from attaching to or penetrating the host cell.
Immunomodulators induce production of host cell enzymes, which stop
viral reproduction. Integrase strand transfer inhibitors prevent
integration of the viral DNA into the host DNA by inhibiting the viral
enzyme integrase. Neuraminidase inhibitors block viral enzymes and
inhibit reproduction of the viruses.
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adamantane antivirals
antiviral boosters
antiviral combinations
antiviral interferons
chemokine receptor antagonist
integrase strand transfer inhibitor
miscellaneous antivirals
neuraminidase inhibitors
NNRTIs
NS5A inhibitors
nucleoside reverse transcriptase inhibitors (NRTIs)
protease inhibitors
purine nucleosides
• Adamantane antivirals are only active against influenza A virus,
an RNA virus, but has no action against influenza B virus. A viral
membrane protein, M2, functions as an ion channel at two
stages of the viral replication within the host cell. These stages
are the fusion of viral membrane and endosome membrane,
and the assembly and release of new virions. Adamantane
antivirals block this ion channel.
• Antiviral boosters are drugs that are used in conjunction with
other specific antiviral drugs to enhance or increase their effect
• Norvir
generic name: ritonavir
• Antiviral combinations have more than one antiviral agent in the one pill or
dose. Using a combination of antiviral agents reduces the risk of resistant
virus strains from emerging.
• Antiviral agents are used to inhibit production of viruses that cause disease.
Most antiviral agents are only effective while the virus is replicating.
• It is difficult to find medicines that are selective for the virus as viruses share
most of the metabolic processes of the host cell. However, some enzymes are
only present in viruses and these are potential targets for drugs.
• Agents that inhibit the transcription of the viral genome are DNA polymerase
inhibitors and reverse transcriptase inhibitors. Protease inhibitors inhibit the
post-translational events. Other antiviral agents inhibit the virus from
attaching to or penetrating the host cell. Immunomodulators induce
production of host cell enzymes, which stop viral reproduction. Integrase
strand transfer inhibitors prevent integration of the viral DNA into the host
DNA by inhibiting the viral enzyme integrase. Neuraminidase inhibitors block
• viral enzymes and inhibit reproduction of the viruses.
• Epzicom (Pro, More...)
generic name: abacavir/lamivudine
• Natural interferons are produced by lymphocytes as part of an
immunological response to viral antigens. Synthetic interferons,
made by recombinant DNA technology, are used as antiviral
agents to treat infections such as hepatitis and herpes zoster
virus.
• Interferons induce the production of enzymes in the ribosomes of
the host cells and inhibit the translation of viral mRNA into viral
proteins, therefore stop viral reproduction.
• Chemokine receptor antagonists inhibit the entry of human
immunodeficiency virus (HIV) into the host cell. Two chemokine
receptors, CXCR4 and CCR5, are necessary for the virus to
enter the cell, so by inhibiting these chemokine receptors the
disease can be slowed.
• Protease inhibitors are synthetic drugs that inhibit the action of
HIV-1 protease, an enzyme that cleaves two precursor proteins
into smaller fragments. These fragments are needed for viral
growth, infectivity and replication. Protease inhibitors bind to
the active site of the protease enzyme and prevent the
maturation of the newly produced virions so that they remain
non-infectious.
• Protease inhibitors are used in the treatment of human
immunodeficiency virus (HIV infection) and acquired immune
deficiency syndrome (AIDS).
• Purine nucleosides are antiviral agents that have selective
activity against herpes simplex virus types 1 (cold sores) and 2
(genital herpes) and varicella zoster virus (chicken pox).
• The purine nucleoside molecule is converted to a
monophosphate by viral thymidine kinases. The monophosphate
is then converted to diphosphate and then into a triphosphate
form by cellular enzymes. The triphosphate form blocks the
replication of viral DNA by inhibiting viral DNA polymerase
and terminating the growing viral DNA chain.
• These purine nucleoside analogues mimics guanosine nucleosides in
their chemical structures and includes vidarabine acyclovir, and
ganciclovir
• Mechanisms of actions
• • Vidarabine is phosphorylated by cellular kinases to a triphosphate
compound, which is an inhibitor and a substrate of viral DNA
polymerase.
• • When used as a substrate for viral DNA polymerase, the
phosphrylated compound competitively inhibits dATP leading to the
formation of ‘faulty’DNA.
• • This results in the prevention of DNA synthesis, as phosphodiester
bridges can longer to be built, destabilizing the strand
• Acyclovir is phosphorylated by virus-induced thymidine kinase
to the triphosphate form, which is a better substrate and
inhibitor of viral DNA polymerase,compared with host.
• • Binding to DNA polymerase is irreversible and once
incorporated into viral DNA, the DNA chain is terminated.
• • The mechanism of action of ganciclovir is similar to that of
acyclovir.
• • Herpesviral enzymes are ~20-fold more susceptible
vidarabine compared with host DNA.
• • Vidarabine is effective against chickenpox - varicella, herpes
zoster and herpes simplex.
• • Acyclovir is useful against the herpesvirus family and is
available as an ophthalmic ointment, a topical ointment and
cream, an IV preparation, and oral formulations.
• • Ganciclovir is effective against human cytomegalovirus.
• • Ganciclovir use may cuase neutropenia and
thrombocytopenia, fever, rash, GIT symptoms, confusion and
seizure.
• • Vidarabine may cause bone marrow suppression andCNS
problems when high blood levels are reached.
• Antiviral agents are used to inhibit production of viruses that cause
disease. Most antiviral agents are only effective while the virus is
replicating.
• It is difficult to find medicines that are selective for the virus as viruses
share most of the metabolic processes of the host cell. However, some
enzymes are only present in viruses and these are potential targets
for antiviral drugs
• Agents that inhibit the transcription of the viral genome are DNA
polymerase inhibitors and reverse transcriptase inhibitors. Protease
inhibitors inhibit the post-translational events. Other antiviral agents
inhibit the virus from attaching to or penetrating the host cell.
Immunomodulators induce production of host cell enzymes, which stop
viral reproduction. Integrase strand transfer inhibitors prevent
integration of the viral DNA into the host DNA by inhibiting the viral
enzyme integrase. Neuraminidase inhibitors block viral enzymes and
inhibit reproduction of the viruses.
• Influenza is a disease caused by a member of the
Orthomyxoviridae. Many features are common with those of
the paramyxovirus infections of the respiratory tract.
• Influenza is characterized by fever, myalgia, headache and
pharyngitis. In addition there may be cough and in severe
cases, prostration. There is usually not coryza (runny nose) which
characterizes common cold infections. Infection may be very
mild, even asymptomatic, moderate or very severe.
Source The reservoir is acute infection in other human beings. •
Spread Is rapid via aerial droplets and fomites with inhalation •
into the pharynx or lower respiratory tract.
Incubation Is short: 1-3 days. Rapid spread leads to epidemics •
• Tend to occur in the young, elderly, and persons with
chronic cardio-pulmonary diseases
• Consist of:
• 1. Pneumonia caused by influenza itself; Pneumonia: an inflammatory
condition of the lungs in which they become obstructed with fluid, causing difficult breathing and possibly suffocation. Pneumonia
may be caused by bacteria, viruses, fungi, or chemical agents.
• 2. Pneumonia caused by bacteria- Haemophilus
influenzae- Staphylococcus aureus- Streptococcus
pneuminiae
• 3. Other viral superinfection, eg. Adenovirus.Overall
death rates increase in times of influenza epidemics.
Epidemiology
Influenza A virus is essentially an avian virus that has "recently"
crossed into mammals. Birds have the greatest number and range
of influenza strains. Avian haemagglutinins sometimes appear in
pig human and horse influenza strains.
• Every now and then (10 - 15 years) a major new pandemic
strain appears in man, with a totally new HA and sometimes a
new NA as well (antigenic shift). This variant causes a major
epidemic around the world (pandemic).
•Over the subsequent years this strain undergoes minor changes
(antigenic drift) every two to three years, probably driven by
selective antibody pressure in the populations of humans infected.
Influenza A Evolution
1874 --- (H3N8)
1890 --- (H2N2) .........................Pandemic
1902 --- (H3N2)
1918 --- (H1N1)..........................Pandemic
1933 --- (H1N1)..........................First strains isolated
1947 --- (H1N1)..........................Variation detected
1957 --- (H2N2).........................."Asian" Flu pandemic
1968 --- (H3N2).........................."Hong Kong" Flu pandemic
1976 --- (H1N1).........................."Swine" Flu, non-epidemic
1977 --- (H1N1) + (H3N2)........."Russian" Flu epidemic
This constant antigenic change down the years
means that new vaccines have to be made on a
regular basis.
New influenza strains spread rapidly in children in
schools and in places where people crowd together.
Influenza epidemics may cause economically
significant absenteeism.
The final stage in the life cycle of a virus is the release of completed viruses
from the host cell, and this step has also been targeted by antiviral drug
developers. Two drugs named zanamivir and oseltamivir that have been
recently introduced to treat influenza prevent the release of viral particles by
blocking a molecule named neuraminidase that is found on the surface of flu
viruses, and also seems to be constant across a wide range of flu strains.
Most attention has been given to oseltamivir (Tamiflu) because it is a tablet,
which is easy to administer. Zanamavir (relenza) is administered as a dry
powder inhaler much like some asthma inhalers. An intravenous version of
Relenza has been administered to volunteers under study conditions but it is
not yet approved or in production. Both drugs can be used to treat influenza;
they are also both approved for the prevention of influenza. These drugs are
also effective against all strains of influenza A, unlike vaccines which are
specific only to the strain for which they were designed. Both medications are
well tolerated with few side effects, although there is concern over the
possibility of psychological effects of Tamiflu and there may be occasional
problems with asthmatics who use Relenza.
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Unique features
2 proteins on surface of virus bind with 2 sites on CD4+ cell
Virus infiltrates into genetic material
Reverse transcriptase enzyme enables virus to become double
stranded DNA
• Once double-stranded DNA, like the host cell, HIV can infiltrate
cell nucleus of target cell
• Gains entry into target cell nucleus with aid of Integrase
• Following integration and replication, long protein chain is
cleaved. Pieces then form into new viral particle
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Nucleoside reverse transcriptase inhibitors
Nucleotide reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Entry inhibitors