Inhibition (HIV Protease with Crixivan)
21" h x 29" w
Inhibition, which has played a part in shaping human history, also acts at the molecular level. Researchers looking for cures or treatments for infections or cancers look for chinks in the armor of a virus, bacterium, or tumor cell - key processes which can be blocked by using inhibition.
The ribbons in this work represent the two (identical) protein molecules known as HIV protease, an HIV enzyme which the virus requires for replication. The development of Merck's Indinavir (displayed in red, white, and light blue, and sitting in the center of the enzyme, blocking it) and other inhibitors of the protease, was a huge advance in the treatment of this infectious disease; these drugs inhibited the protease and blocked replication of the virus.
HIV-protease with Merck's inhibitor, Indinavir, [Crixivan] [Hiv_crix.pdb]
The emergence of HIV, in the 1980s, provoked a strong push to develop anti-HIV drugs. HIV uses a cutting enzyme, HIV protease, to break down large HIV proteins into smaller units which must be assembled to create new viruses. The HIV protease is essential to replication of the virus. By blocking this cutting enzyme, Merck's Indinavir (a.k.a. Crixivan) and other HIV protease inhibitors block viral production. These drugs were among the first to be produced by "rational drug design" - using the known structure of the target (HIV protease) to computer-design compounds capable of blocking its action.
These inhibitors successfully altered the outcome of HIV, extending the expected lifespan of infected individuals - the inspiration for this piece, and an example of why knowing protein structure is so important.
This work shows a molecular model of the HIV protease as two "ribbons" representing the two identical polypeptide chains that make up the HIV protease. Indinavir is shown in “spacefill” model with the standard molecular color scheme: oxygens as red, nitrogens as blue, and carbons as grey/white. The interaction between Indinavir and the protease depends on chemical bonds between the inhibitor and the two amino acids at the "active site" of the enzyme, one from each polypeptide chain: aspartate 25, also shown in spacefill.