In this article we will discuss about the strategies and types of antiviral drugs.
Strategies of Antiviral Drugs:
Antibiotics which have revolutionized the control of diseases caused by bacteria and some other pathogenic agents are totally ineffective against viruses, because the viruses do not have a cell and they are heavily dependent on the host cell for multiplication.
Therefore, the target sites at which antibiotics act in bacteria are lacking in viruses. For example, the 3-lactam antibiotics like penicillins and cephalosporin’s or cephamycins interfere with bacterial cell wall, a structure which is absent in animal cells.
Many antibiotics are targeted against prokaryotic protein synthesis. Thus, antibiotics can selectively attack those peculiarities of bacteria which are absent in the host cells. Development of effective antiviral drugs similarly depends on searching out suitable target sites.
The possible targets for antiviral drugs could be:
(i) Attachment of the virion on the host cell membrane. If the virus is prevented from attachment to the target cell, the virus cannot multiply or cause any damage. As the virions interact with specific receptors present on the surface of the host cell, one strategy could be an antiviral drug which resembles the receptor chemically so that the virion mistakes it as a true receptor and binds to it instead of the target cell.
An alternative approach could be to block the surface proteins of the virions, so that they can no longer interact with the host receptor sites. Antibodies produced against viral surface antigens could serve such a purpose effectively.
(ii) Many animal viruses enter the host cells by an endocytic pathway in which the virion — either with or without envelope — are endocytosed, and the un-coating and release of nucleic acid take place in the endocytic vesicle. A possible target site of an antiviral drug could be prevention of un-coating.
(iii) Some viruses, like the retroviruses, carry enzymes in their virions which are needed for their replication and which are absent in the host cell. So, another strategy of antiviral drugs could be to inhibit those viral enzymes, so that replication of the virus could be prevented. Generally, nucleotide analogues possess attractive possibilities to be used as such inhibitors.
The possible target sites for antiviral drugs are schematically represented in Fig. 6.34:
Types of Antiviral Drugs:
Amantadine is a low molecular weight compound which is effective against influenza virus A. It prevents attachment as well as un-coating of endocytosed virions. It binds to the viral matrix proteins of influenza virus and thereby prevents the conformational changes required for un-coating. A related compound Rimantadine has a similar effect on influenza virus. A number of nucleoside analogues have been used as antiviral drugs. Among these are acyclovir, idoxuridine, ribavirin, vidarabine, trifluridine, azidothymidine etc.
Acyclovir is an analogue of deoxyguanosine (Fig. 6.35):
Because of the structural similarity of acyclovir and deoxyguanosine, the viral enzyme, nucleoside kinase phosphorylates acyclovir to its phosphate forming a false nucleotide which cannot be incorporated into DNA i.e. DNA polymerization is inhibited. Acyclovir derivatives, like famciclovir and ganciclovir are similar in mode of action (Fig. 6.36).
Acyclovir and its derivatives have been found to be effective against herpes virus infections, particularly genital herpes. It has also effect on chicken pox. Other nucleoside analogues have also been used as antiviral drugs, like idoxuridine (5′-iodo-deoxyuridine), trifluridine, vidarabine (adenine arabinoside) etc.
Idoxuridine is a thymidine analogue (Fig. 6.37) and is incorporated into viral DNA blocking further polymerisation of DNA. Vidarabine has structural similarity with deoxyadenosine and has a similar effect on viral DNA synthesis as idoxuridine. These drugs are mainly used in infections caused by herpes virus.
An important strategy of inhibiting retroviruses such as HIV is to block the activity of reverse transcriptase, the viral enzyme required for synthesis of DNA from the genomic RNA of these viruses. Reverse transcriptase is absent in the host cells. Several chemotherapeutic agents have been developed as potential reverse transcriptase inhibitor, such as zidovudine (azidothymidine, AZT), didanosine and zalcitabine.
These agents inhibit synthesis of DNA from viral RNA by specifically blocking the activity of reverse transcriptase. They have been found useful in HIV infection causing AIDS. Zidovudine structurally resembles thymidine (Fig. 6.38).
Didanosine and zalcitabine are less toxic than zidovudine. These agents act as competitive inhibitors of thymidine in the reverse transcription of viral genomic RNA to ds-DNA. As this step is essential for viral replication, these agents can effectively stop viral multiplication in AIDS patients.
The mechanism of action appears to be the incorporation of the drug in the elongating DNA chain in place of thymidine, thereby inhibiting further addition of nucleotide. The presence of the azide group in 3′-position in place of an OH-group which is essential for DNA polymerisation prevents chain elongation. Didanosine (dideoxyinosine) and zalcitabine (dideoxy- cytidine) have a similar mode of action.
Another agent which inhibits reverse transcription of retroviruses is foscarnet (phosphonoformic acid). It inhibits DNA polymerization by binding to the pyrophosphate receptor, so that incorporation of nucleotides from the precursor nucleoside triphosphates into DNA cannot take place. Other reverse transcriptase inhibiting drugs include nevirapine and delaviridine.
Another approach to combat HIV is to inhibit the viral protease which is essential for cleaving polyprotein molecules into fragments that are used for assembly of new viral particles. The protease inhibitors developed as potential drugs for HIV therapy include indinavir, saquinavir and ritonavir.
The protease inhibitors are amino acid analogues and they act as competitive inhibitors in the viral protease reaction. As a result, the long protein molecules cannot be cleaved to smaller ones required for virion assembly. Thus, assembly of progeny virions is prevented.
One of the best strategies to control a viral disease would be to prevent the virus from entering the target host cells. This could be achieved through vaccination which induces development of antibodies that would react with the surface proteins of viral particles and would stop their entry into the host cell. In recent times, antiviral drugs have been synthesized which act in a more or less similar way.
One class of these drugs is the neuraminidase inhibitors which are being used against influenza virus. The virions of influenza virus contain two types of spikes on their envelope — one type contains haemagglutinin activity and the other type contains neuraminidase activity.
These spikes take part in attachment of influenza virus to the cells of the respiratory tract of the host. Neuraminidase inhibitors, like zanamivir and oseltamivir phosphate, block attachment of influenza virus particles by clogging the sites of the host cell surface where the virions could attach.
The development of these anti-influenza drugs was only possible because the precise knowledge of biochemistry of attachment of the virus to the host cell surface was known. This proves that with extension of knowledge of viral infection in future, more and more effective antiviral drugs would be discovered. But till now, the most effective measure against viral diseases continues to be vaccination which induces both humoral (through antibodies) and cell-mediated (through killer T-lymphocytes) immunity in the body.
Most vaccines against viral diseases utilize inactivated or attenuated viruses. Such vaccines e.g. the Salk vaccine against poliomyelitis, uses live viruses inactivated by formaldehyde, or Sabin vaccine, also against the same disease, uses attenuated viruses.
These vaccines have certain amount of risk, though very negligible, because the inactivation may not be 100 per cent, or in rare cases attenuated viruses may revert to their original pathogenic form. In more recent years, sub-unit vaccines have been developed by genetic engineering.
For example, hepatitis B viral vaccine has been prepared by transferring the viral gene coding a capsid protein to yeast. The transgenic yeast produces the viral capsid protein which after isolation and purification has been used to prepare the hepatitis B virus vaccine. The vaccine containing the capsid protein induces immunity against hepatitis B infection. These vaccines are sometimes called DNA vaccines, because they involve recombinant DNA technology.