Current Topics in Chemistry - Bruice

Dr. Glaser's "Chemistry is in the News"
To Accompany Bruice, Organic Chemistry, 3/e.
Chapter 22. Catalysis.

For each of the following questions, please refer to the following article:

FUTURE OF AIDS THERAPY SEEN IN COMBINING PROTEASE INHIBITORS
by N.N. (Medical Tribune News Service, 1997)

Editorial Comments

The JOHNS HOPKINS AIDS Service is an excellent internet site worthwhile visiting. There is plenty of detailed information about all aspects of AIDS infection including treatment options. The best option is "Antiretroviral Therapy". The goal of "Antiretroviral Therapy" for HIV infected patients is the reduction of the level of HIV RNA to as low a level as possible for as long as possible. A list of FDA approved antiretroviral drugs for HIV treatment contains some 19 compounds (as of March 2000). Three types of drugs used in antiretroviral therapy and these are: nucleoside analogs, non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors.

(1) The nucleoside analogs include RETROVIR which contains Zidovudine
    (AZT,ZDV).  Another important drug in this group is EPIVIR which
    contains Lamivudine (3TC). 

(2) The non-nucleoside reverse transcriptase inhibitors are Nevirapine 
    (VIRAMUNE), Delavirdine (RESCRIPTOR), and Efavirenz (SUSTIVA).

(3) Protease inhibitors include ritonavir (NORVIR by Abbott), saquinavir 
    (INVIRASE and FORTOVASE by LaRoche), and indinavir (CRIXIVAN by Merck).

The protease inhibitors turned out to be really powerful. Usually the protease inhibitor is used in combination with drugs of the first two types and the result is casually referred to as an "AIDS cocktail". This cocktail can be achieved by swallowing different tablets or by combination of all drugs into one table of the cocktail. In 1997, the Food and Drug Administration approved the first combination AIDS tablet. Glaxo Wellcome combined the drugs AZT (a nucleoside analog, 3'-azido-3'-deoxythymidine) and 3TC (a non-nucleoside reverse transcriptase inhibitors) with protease inhibitors like Crixivan or Norvir.

"There was unprecedented optimism at the 11th International Conference on AIDS in Vancouver, B.C., last summer [summer of 1996]," wrote Jim Puzzanghera in the Seattle Times of September 30, 1997, "followed by reports of dramatic decreases in AIDS-related deaths and the first scientific studies showing the three-drug cocktail could pummel the virus to undetectable levels. Stories of the dramatic recoveries led to a drop in donations to AIDS charities and a flurry of optimistic headlines, such as Newsweek's "End of AIDS?"

Well, not quite. It turns out that some 30 percent of AIDS patients receiving the protease inhibitors do not respond to treatment. Going one step further, trials are now underway to use second-generation cocktails that contain two protease inhibitors. First results seem promising and there are indications that "dual protease inhibitor therapy is going to be very popular in the future".

How do the AIDS drugs work? The Cells Alive! website includes pertinent information on viruses and an excellent article on the mechanisms of HIV infection. The virus attack involves several stages: Attachment to cell surface, reverse transcription of viral RNA to DNA, integration of the viral DNA into cellular DNA and transcription to form copies of viral RNA, translation of the RNA into proteins, the cleaving of the protein by way of viral protease into the individual enzymes, and assembly and budding. The JOHNS HOPKINS AIDS Service has an excellent article on the Life Cycle of HIV Infection which includes an outstanding animation.

Pertinent Text References
Chapter 22. Catalysis.
Chapter 22.8. Catalysis in Biological Reactions.
Chapter 25.17. Rational Drug Design.

Questions

Question 1: Explain in your own words the terms "protease" and "protease inhibitor".

Answer 1: A protease is an enzyme that catalyzes the cleavage of an amide bond in a peptide. A protease inhibitor is any molecule that binds to protease in such a way as to curtail the catalytic action of the protease.

Question 2: The visualization center to Chapter 22 contains the X-ray structure of a complex between HIV-1 protease and an inhibitor. View the protease and, to enhance the visual inspection, write down the structure formula of that inhibitor.

Answer 2: See visualization center to Chapter 22.

Question 3: Look up and write down the molecular structures of Norvir, Invirase, and Fortovase. What structural characteristics do these compounds have in common?

Answer 3: See ChemFinder. Backbone containing several amide bonds, arenes in the side chains.

Question 4: Describe in your own words how a virus multiplies. In particular, explain the function of the protease in the process. Does the protease inhibitor kill the virus?

Answer 4: Review the website on HIV infection at Cells Alive! The protease does not kill the virus. Rather, the protease inhibitor suppresses the multiplication and the continued infection of other cells.

Chemistry & Society.
These new drugs will help some. Others will not repond to the drugs. Still others will never get a chance to try the drugs. Have no illusions, AIDS is not contained, AIDS has not been reduced to a "manageable disease". "The world today is confronted with the greatest health crisis in human history," says Congressmam James Leach of Iowa in the article U.S. Congress sends Clinton bill creating African AIDS trust fund. What is the goal of establishing this trust fund?