Three basic approaches are taken to control viral diseases. Vaccination is used to try to prevent and control the spread of disease. Chemotherapy (the focus of pharmacology) is used to treat the symptoms of viral illness and to try to eliminate the virus from the body. Finally, stimulation of the host’s natural resistance mechanisms is used to shorten the duration of illness.
The problems with chemotherapy are similar to those discussed for antimicrobial and antifungal agents. Anytime we are trying to kill an invading (foreign) organism, there is the problem of the drug recognizing and distinguishing the invading organism from the host. To understand the antiviral agents, it is necessary to review the life cycle of viruses and imagine sites where drugs could interfere or block:
Attachment and penetration of the virus to the host cell.
Uncoating of the viral genome within the host cell.
Synthesis of viral components within the host cell.
Assembly of viral particles.
Release of the virus to spread and invade other cells.
Most of the drugs that are currently available block specific viral proteins that are involved in synthesis of viral components within the host cell.
|Reverse Transcriptase Inhibitors ||Protease Inhibitors ||Fusion and Entry Inhibitors |
|NRTIs ||NNRTIs ||nucleotide ||atazanavir ||enfuvirtide |
|abacavir ||delavirdine ||tenofovir ||darunavir ||maraviroc |
|didanosine ||efavirenz || ||fosamprenavir || |
|etravirine || ||indinavir ||Integrase |
|nevirapine || ||lopinavir ||Inhibitors |
| || ||nelfinavir ||dolutegravir |
| || ||ritonavir ||elvitegravir |
| || || ||saquinavir ||raltegravir |
| || || ||tipranavir || |
As a reminder, human immunodeficiency virus (HIV), which is the virus that causes AIDS, is an RNA retrovirus. This means that it has a specific enzyme called reverse transcriptase. This is a major target of drugs with efficacy against HIV.
The nucleoside (NRTIs), nucleotide, and nonnucleoside (NNRTIs) reverse transcriptase inhibitors (RT inhibitors) all inhibit the formation of viral DNA from RNA by reverse transcriptase.
The RT inhibitors are divided into several groups based on whether they are structurally related to nucleoside/nucleotides or not. The nucleoside analogues are related to thymidine and adenosine and, after triple phosphorylation, are incorporated into viral DNA during the reverse transcription of the viral RNA. But because they are not exactly the same as the native nucleosides, there is early termination of DNA elongation. The nucleotide RT inhibitor works in a similar manner, except that it is already phosphorylated once. The nonnucleoside inhibitors also stop the reverse transcriptase enzyme, but not by mimicking the natural nucleosides.
Mutation of the reverse transcriptase enzyme is very rapid. The use of at least two RT inhibitors simultaneously slows the emergence of resistant virus.
The protease inhibitors interfere with processing of the viral protein, thus preventing formation of new viral particles.