CLINICAL APPLICATIONS AND MODES OF ACTION OF ANTIVIRAL AGENTS

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Antiviral agents are antimicrobial agents that specifically inhibit the replication of viruses in living cells (inclusive of human cells affected by viral particles). These antimicrobial agents like antifungal agents have poor or low selective toxicity. This is because viruses only live in living cells i.e. they are obligate intracellular parasites and cannot survive outside a living system. Because of their intracellular nature, antiviral drugs targeted at pathogenic viruses not only inhibit viral replication but they also interfere with the cellular and metabolic activities of the recipient human or animal cells. Viruses live inside their host cells; and they depend mainly on the biosynthetic and enzymatic machinery of their host cells which they overwhelm to direct their own replication processes in vivo. This is why most of the antiviral agents end up harming the recipient host aside their normal antimicrobial onslaught on their target viruses.

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The number of antiviral agents like antifungal agents is very small, and this is because most drugs used for antiviral therapy also adversely affect the animal or human host taking them since the organism lives inside the cells of the recipient animal or human host. Since viruses are intracellular parasites and lives inside the host cells, most antiviral drugs target specific phases in the life cycle and/or replication processes of the viral particle while others exhibit their antimicrobial activity by targeting the nucleic acids of the viruses (either DNA or RNA) or by preventing the adherence of the viral agent to the host cells. Apart from synthetic antiviral agents used for the clinical management of some viral infections, the human body produces chemical substances that possess antiviral activity. These natural substances produced by the body and which inhibit the nefarious activities of viruses in vivo are generally known as immunomodulators.

Immunomodulators are chemical substances which boosts the body’s immune system (particularly the T-cells) in order to direct the host’s immunological response to an invading viral agent. Immunomodulators o immunomodulants can also be produced artificially, and their main function in the body is to interfere with viral replication processes in vivo i.e. inside the infected cells of living organisms. Interferon (IFN) is a typical example of an immunomodulant; and they are proteinous substances produced by viral infected cells in response to viral invasion of host cells. Interferons help to reduce the spread of viruses in the body by interfering with their replication, and they also boost the body’s response to antigenic substances (e.g. microorganisms). Interferons (IFNs) are examples of cytokines. They have the ability to inhibit the replicative ability of many viruses; and they are clinically relevant for treating some viral infections including those caused by the hepatitis virus and influenza virus.

Recombinant forms of IFNs also exist for clinical use, but these antiviral agents are expensive and are only used to treat a limited number of microbial infections (inclusive of viral infections). IFNs are generally produced by viral infected cells and they mainly interfere with viral mRNA during viral replication. Unlike other microorganisms (inclusive of bacteria, fungi, algae and protozoa) which contain both DNA and RNA in their genome as nucleic acids, a viral particle (virion) either contains DNA or RNA as its genetic makeup or genome. The development of viral-specific antiviral agent is complicated and difficult because drugs used for the treatment of viral infections (which are small at the moment compared to the many antibacterial agents) apart from targeting the virion also adversely leave untoward effects in the recipient host cells which harbours the viral particle. Also, viruses have high mutation ability that makes most antiviral agents inefficacious in vivo.Most antiviral agents target cellular DNA in their quest for invading viral particles, and this limits the number of effective viral agents with higher selective toxicity used in clinical medicine. Despite their low selective toxicity, antiviral agents target specific sites and functions supposed to be more prevalent in the virion than in the host cell. For example, the rate at which viruses synthesize their nucleic acids (DNA or RNA) is faster compared to human or animal hosts whose cellular DNA synthesis may be slower. Viruses are fast replicating organisms and they also mutate in these processes into various forms that may be missed by antiviral agents.

Summarized mode of action of antiviral agents

Some of the mode of action of antiviral agents include: inhibition of viral attachment, inhibition of viral nucleic acid synthesis, and inhibition of viral enzymes such as protease. The various target sites and/or mode of action of antiviral agents are briefly highlighted in this section.

  • Viral attachment inhibition: Viral attachment to host cells is often the first prerequisite to their entry into infected cells. Once they attach to specific receptors on their target host cell, viruses penetrate the outer cell structure and start to uncoat within the host cell. Viral attachment, penetration and uncoating are often the first step in the replication of viruses within living host cells. Amantadines, rimantadine and enfuvirtide are examples of antiviral agents that inhibit or interfere with viral penetration and uncoating in living cells.     
  • Inhibition of viral nucleic acid synthesis: Viruses as earlier said only have one type of nucleic acid. It is either the virus contains DNA, and is called a DNA virus or its nucleic acid is RNA, and is called an RNA virus. Both DNA and RNA (found separately in each viral particle or virion) are critical in the life cycle of viruses. They play important roles in the entire replication processes of viruses because these macromolecules direct the activities of the virus. Antiviral agents that interfere with the synthesis of viral nucleic acids (either DNA or RNA) act as nucleoside analogues i.e. they resemble the nucleoside molecules (inclusive of guanosine, adenosine, cytidine and thymidine) required by potential viral particles for the synthesis of their own nucleic acids (DNA or RNA) iv vivo. Antiviral agents in this category specifically interfere with the activities of enzymes (e.g. polymerases) that direct viral DNA or RNA synthesis; and their inclusion or incorporation into viral nucleic acids automatically inhibit or obstruct the biosynthesis of DNA or RNA in the target virion. A wide variety of antiviral agents are nucleoside analogues or inhibitors of viral nucleic acid synthesis. Examples of antiviral agents that are nucleoside analogues include acyclovir, zidovudine or azidothymidine (AZT), cidofovir, ribavirin, lamivudine, and zalcitabine or dideoxycytidine. AZT, a reverse-transcriptase (RT) inhibitor is used to manage HIV/AIDS patients. The drug (i.e. zidovudine) interferes with RT in retroviruses (e.g. HIV) in order to inhibit their activity in viruses. AZT is selectively toxic in action because the human cell lacks reverse transcriptase enzymes. RT is an RNA-dependent-DNA-polymerase enzyme that is mainly responsible for the synthesis of viral DNA from viral RNA (which serves as a template for this purpose) in retroviruses (particularly HIV). 
  • Other viral agents: Nelfinavir, saquinavir, indinavir and ritonavir are viral protease synthesis inhibitors. Antiviral agents that are in this category (i.e. protease inhibitors) are novel antiviral agents. They inhibit viral assemblage and release from infected host cells which is the primary function of protease enzymes in viruses. Viral particles easily develop resistance to protease inhibitors, thus they should be used in combination with other antiviral agents (e.g. AZT) especially in HIV/AIDS patients. 

FURTHER READING

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India. 

Block S.S (2001). Disinfection, sterilization and preservation. 5th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Ejikeugwu Chika, Iroha Ifeanyichukwu, Adikwu Michael and Esimone Charles (2013). Susceptibility and Detection of Extended Spectrum β-Lactamase Enzymes from Otitis Media Pathogens. American Journal of Infectious Diseases. 9(1):24-29.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg.

Russell A.D and Chopra I (1996). Understanding antibacterial action and resistance. 2nd edition. Ellis Horwood Publishers, New York, USA.

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