HIV PR inhibitors: Most enzyme inhibitors are
peptide-mimicking compounds that are transition
state analogs. In other words, these compounds
resemble the transition state configuration of the
natural substrate of the HIV PR. As a result, the
inhibitors bind the enzyme much more tightly than the
natural substrate (since the substrate must be
distorted in order to assume its transition state
configuration). These compounds are therefore
competitive enzyme inhibitors, which are classified
according to the symmetry of their structures. For
example, Merck's inhibitor, Indinavir, and Roche's
inhibitor, Saquinavir are not symmetrical, while
Abbott's ritonavir has a high degree of symmetry.
HIV PR inhibitors: Most enzyme inhibitors are
peptide-mimicking compounds that are transition
state analogs. In other words, these compounds
resemble the transition state configuration of the
natural substrate of the HIV PR. As a result, the
inhibitors bind the enzyme much more tightly than the
natural substrate (since the substrate must be
distorted in order to assume its transition state
configuration). These compounds are therefore
competitive enzyme inhibitors, which are classified
according to the symmetry of their structures. For
example, Merck's inhibitor, Indinavir, and Roche's
inhibitor, Saquinavir are not symmetrical, while
Abbott's ritonavir has a high degree of symmetry.
In the structure shown here, indinavir has replaced the
substrate. Indinavir is in red, and the active site Phe
residues are in white:
Drug resistance: Genetic resistance of HIV-1 strains
to protease inhibitors can occur. In the case of
indinavir this is mediated by in large part by a key
mutation at amino acid residue 82 (V82 -> A, F or T).
As above, indinavir is in red, and the active site Phe
residues are in white. Valine 82 is shown in yellow:
Importantly, viral mutations which confer resistance to
several of the other protease inhibitors are NOT the
same as those which confer resistance to indinavir.
For example, the key resistance mutation for
saquinavir maps to amino acid residue 90 (shown in
yellow; the active site Asp residues are in white):
Likewise, the key resistance mutation for nelfinavir
maps to amino acid residue 30 (shown in yellow; the
active site Asp residues are in white):
Other concerns/problems: An addition problem
with protease blockers is their oral bioavailability.
This has been a major problem in their development
(in many cases, 5% or less of ingested drug reaches
the circulation). In addition, the ability of these drugs to
enter the central nervous system (ie, to cross the
blood-brain barrier) appears to be quite limited in
many cases.
For more information, see Erickson and Wlodawer,
Annu. Rev. Biochem. 62:543-585, 1993.