Biomedical Engineering Reference
In-Depth Information
2.3 HIV PROTEASE INHIBITORS
When in 1984 it was discovered that the human immunovirus (HIV) caused AIDS it was the start of
an intensive drug-hunting process. The DNA in the virus encodes for a number of enzymes, e.g., a
reverse transcriptase, an integrase, and a protease. Each of these represented a potential drug target,
and drugs have been developed subsequently for each of the enzymes. Presently, cocktails of inhibi-
tors against at least two of these enzymes are used therapeutically. In the following text, we will
concentrate on the HIV-1 protease and how biostructure-based design has been applied extensively
to this target.
The i rst 3D structure of an HIV-1 protease in complex with an inhibitor, MVT-101, was reported
shortly after it had been shown that inhibition of the HIV-1 protease prevented the virus in pro-
ducing new virions. MVT-101 binds to the enzyme in an extended conformation and forms a net-
work of hydrogen bonds between the ligand and enzyme (Figure 2.7). Hydrophobic substituents on
the inhibitor occupy hydrophobic pockets in the enzyme, and a water molecule mediates contact
between the inhibitor and two residues in two l exible beta-sheets, normally referred to as the l aps.
Today, close to 300 structures of complexes between HIV-1 protease and ligands have been deter-
mined, which makes HIV-1 protease one of the structurally most extensively studied proteins.
The i rst HIV-1 protease inhibitors like, e.g., indinavir (Crixivan), neli navir (Viracept), and
saquinavir (Invirase, Fortovase) (Figure 2.8) were derived from the polypeptide sequences cleaved
by the protease in the HIV. Accordingly, they were very peptide-like and had poor bioavailability.
Unfortunately, the HIV rapidly developed resistance against these i rst-generation inhibitors.
The shapes of the hydrophobic pockets are sensitive to mutations in the enzyme and accordingly,
the virus could easily prevent an inhibitor from binding by mutation of residues forming the hydro-
phobic pockets.
(A)
(B)
H
2
N
NH
NH
3.3
2.7
O
O
N
N
N
2.5
3.0
NH
2
CH
3
H
H
H
O
O
O
O
OH
(C)
(D)
H
2
N
O
FIGURE 2.7
3D structure of the HIV-1 protease with bound MVT-101 (pdb-code 4HVP). (A) Side view
showing that the active form of the HIV-1 protease is a homodimer (colored red and green, respectively) and
that the inhibitor MVT-101 binds between the two monomers. (B) Top view showing the extended form of
the inhibitor and that the inhibitor via a structural water molecule (cyan) binds to the l aps. (C) The structural
water molecule makes four hydrogen bonds to the inhibitor and to Ile50 in the l aps. (D) Chemical structure
of MVT-101.
