HIV - 1 Protease - An AIDS Drug Target



The proteins that comprise the human immunodeficiency virus (HIV) are produced in the form of long "polyproteins." These polyproteins must be cleaved to yield the active protein components of the mature virus. The HIV-1 protease is a novel aspartic protease that functions to cleave the nascent polyproteins during viral replication. When viewed as a space-filling model , the novel structural features of this enzyme are not readily apparent.


However, a ribbon structure quickly reveals the dimeric nature of this protein. Each monomer subunit contains two twisted beta sheets and a small alpha helix .


The HIV-1 protease consists of two identical polypeptides of 99 amino acids, each chain having an N-terminal Pro and C-terminal Phe . The active site cleft is "covered" by flaps that extend from Met-46 to Lys-55 .


Catalysis of protein chain cleavage by this protease is mediated by twin Asp-25 residues juxtaposed in the active site. These two aspartates are said to form a "catalytic diad" . One of these carboxyl groups exhibits an unusually low pKa of 3.3 and the other displays an unusually high pKa of 5.3.

This catalytic diad of aspartate residues normally interacts with the amide bond to be cleaved in the polypeptide substrate.

In the structure shown here, Crixivan, the new AIDS drug, made by Merck, has replaced the substrate, inhibiting the protease.

Crixivan and the other new AIDS drugs, known as "protease inhibitors" elicit highly specific inhibition of the HIV protease. These drugs must also be able to easily cross the cell membrane, so that therapeutically effective concentrations of the drug can be delivered to diseased cells.

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