Fact Sheet: Number 5 (1995)
The treatment of HIV/AIDS depends upon the use of a variety of anti-AIDS agents. Antiviral agents are used to attack HIV and prevent its replication. In addition, numerous other medicines, including antibiotics, antifungal agents, and anti-cancer drugs are used to treat AIDS-related diseases. Often a combination of all of these drugs (antiviral agents, antibiotics, antifungal agents, and anti-cancer agents) is used either together or in sequence.
The development of new medicines to attack HIV is a major goal of research in the pharmaceutical industry. Several steps in the life cycle of HIV are being targeted. It is hoped that a combination of drugs targeted at different steps in the viral life cycle or targeted at different aspects of the same step will result in an effective therapeutic approach to inhibiting viral growth and the associated diseases which result from the destruction of the immune system by the virus.
HIV infects cells via a receptor on helper T cells, referred to as CD4. The virus attaches, enters the cell, and its RNA genome is transcribed into DNA by reverse transcriptase (RT). The DNA is transcribed to more RNA which is translated into proteins. Some proteins must be cut by proteases to be active. Figure 1 (see below) lists the drug classes which inhibit HIV and their mechanisms of inhibition.
The most researched anti-HIV agents are the RT inhibitors. Zidovudine, commonly known as AZT, was the first of these approved by the Food and Drug Administration (FDA). AZT prolongs life in individuals with AIDS and lengthens the time to progression to full blown AIDS in those with T cells less than 500 without prolonging life. Like most of the RT inhibitors, AZT is a nucleoside analog which blocks RT activity by blocking the site needed to elongate the DNA chain, (i.e. a chain terminator). Other nucleoside RT inhibitors include: didanosine (dDI), zalcitabine (dDC), stavudine (d4T) and 3TC. Toxicities limit the use of these agents. For example, AZT causes anemia and cytopenias; dDI is associated with poor patient tolerance, pancreatitis and peripheral neuropathy; and dDC causes peripheral neuropathy. Nevirapine is an example of another class of RT inhibitor which is not a nucleoside analog. Although resistance develops rapidly when used alone, nevirapine and related drugs may prove useful in combination.
There is a great deal of excitement about the potential effectiveness of the protease inhibitors (the second entry in Table 1). These agents have a completely different mechanism of action. Like the reverse transcriptase inhibitors, protease inhibitors are expected to stop viral replication and prevent further degradation of the immune system. Clearly, the combination of protease inhibitors with reverse transcriptase inhibitors might provide a more effective therapy for HIV. Several protease inhibitors are being developed by major pharmaceutical companies.
Protease inhibitors act by blocking the activation of viral proteins. The discovery of protease inhibitors is a fascinating story of the design of "magic bullets." Initially, the molecular structure of HIV protease was determined using X-ray crystallography. This structure showed that HIV protease is a dimer and provided atomic coordinates of the enzyme. These coordinates are then used to make drawings of potential inhibitors bound to the enzyme. These drawings allow design and synthesis of inhibitors which are usually peptides or peptide mimetics. These inhibitors are then synthesized and tested for their ability to inhibit protease. In addition, attempts are made to determine the X-ray structure of the inhibitor-protease complex. This data is then used to design second and third generation drugs. This process has led to some exciting new drugs which have different molecular structures and excellent potential.
The remaining drugs described in Table 1 are under active investigation, but have not progressed as far as the protease inhibitors. Table 1 lists both drugs approved by the FDA and drugs in clinical trial. These approved drugs form the first line defense against the spread of the viral infection. Sixteen other drugs have also been approved for HIV-related infections. These include agents for the treatment of Kaposi's sarcoma, MAC, PCP, histoplasmosis, toxoplasmosis, and herpes.
As of November 1994, there are an additional 107 AIDS medicines in testing. (See Table 1 below.)
Figure 1 (above) shows that the majority of the AIDS medicines in testing are antiviral agents. However, a significant number of additional medicines/vaccines are in testing. Cytokines are medicines which regulate or modify the growth of specific cells. Immunomodulators modulate the response of the immune system to viruses. Anti-infectives are used to combat AIDS-related infections.
In conclusion, it is important to address the prospects for the development of an anti-HIV vaccine. Clearly, a vaccine is the ultimate method of prevention. The FDA has canceled the clinical trials of two of the early vaccine candidates because of lack of evidence of effectiveness. The development of anti-HIV vaccines is extremely difficult because of the wide range of serotypes of HIV which exist. Until an effective vaccine can be developed, prevention education is the best approach to stop the spread of HIV.
Glossary of Terms Related to AIDS Drug Discovery
- AIDS: Acquired immunodeficiency syndrome
- CMV: Cytomegalovirus - can cause blindness
- Helper T cells: cells in the immune system involved in fighting infections
- Herpes Zoster/Simplex Virus: can infect AIDS patients
- Histoplasmosis: A fungal infection that occurs in AIDS patients. Symptoms include fever, shortness of breath, cough, weight loss, and physical exhaustion
- HIV: Human immunodeficiency virus, the cause of AIDS
- Kaposi's Sarcoma: Skin cancer in AIDS patients
- Lymphoma: Cancer of the lymph system
- MAC: A bacterial infection from myco-bacterium avium which occurs in AIDS patients
- PCP: Pneumocystis carinii pneumonia - a lung infection present in about 80% of all AIDS patients
- Toxoplasmosis: An infection with the protozoa, Toxoplasma gondii, which causes various diseases
Table 1: Drugs Related to Various Steps in the Viral Life Cycle
|Step Targeted||Classification Drug||Example|
|Conversion of Viral RNA (the HIV Genetic Information) to DNA||Reverse Transcripase Inhibitors||AZT, ddI, d4T, Nevirapine|
|Post-translational modification of Viral Proteins||Protease Inhibitors||L-735, 524, SC-52151|
|Integration of Viral DNA into Host Cell Genome||Integrase Inhibitors||Studies in Progress|
|Various Gene Products with Anti-Viral Activity||Gene Therapy||Studies in Progress|
|Viral Uncoating||uncoating Inhibitors||Studies in Progress|
- PhARMA's AIDS Medicines in Development, 100 15th St., Washington, DC 20005 (1994).
- Lunny, E.A. et. al., J. Med. Chem. 37, 2664 (1994).
- S. Thaisrivongs, J. Med. Chem. 37, 3200 (1994).