Antiviral

Antiviral Drugs

General Characteristics of Viruses

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.

Viral Structure

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

Nucleic Acid
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.

Viruses and Cancer

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.

Types of Antiviral agents

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


What are Adamantane antivirals

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.

What are Antiviral boosters

Antiviral boosters are drugs that are used in conjunction with other specific antiviral drugs to enhance or increase their effect
Norvir generic name: ritonavir

What are Antiviral combinations

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

interferons

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 antagonist

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
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

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.

Clinical applications

• 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.


Side effects
• 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.

Miscellaneous antivirals

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

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.

CLINICAL FEATURES

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

Complications

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.

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.
Epidemiology

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.






HIV
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


HIV
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

Drugs for HIV Infection

Nucleoside reverse transcriptase inhibitors
Nucleotide reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Entry inhibitors