This document discusses HIV protease inhibitors. It begins by introducing HIV and HIV protease. HIV protease is a homodimer that catalyzes essential events in the maturation of infective HIV particles. The structure of HIV protease contains an active site with two essential aspartic acid residues. Upon inhibitor binding, residues in flexible flaps undergo movements to interact with the inhibitor. A number of early HIV protease inhibitors are discussed, including diol diamines that entered clinical trials but had limitations. Cyclic urea inhibitors were designed to interact symmetrically with the active site. Three approved HIV protease inhibitors are then briefly described: saquinavir was the first approved, indinavir overcame low bioavailability issues, and ampren

1. Agents acting on HIV Protease
 Submitted by:-
Lakshay Gupta
 Submitted to:-
Dr. Om Silakari

2. Contents
1. HIV
2. HIV Protease
3. Structure of HIV Protease
4. Drug receptor interactions
5. History of drugs
6. Drugs

3. HIV
 The human immunodeficiency virus (HIV) is a
retrovirus belonging to the family of lentiviruses.
Retroviruses can use their RNA and host DNA to make
viral DNA and are known for their long incubation
periods. Like other retroviruses, HIV infects the body,
has a long incubation period (clinical latency), and
ultimately causes the signs and symptoms of disease,
here AIDS. HIV causes severe damage to the immune
system and eventually destroys it by using the DNA of
CD4+ cells to replicate itself. In that process, the virus
eventually destroys the CD4+ cells.

5. HIV Protease
 HIV-P is a symmetrical homodimer of identical 99
residue monomers, structurally and mechanistically
similar to the pseudosymmetric pepsin family of
proteases, whose members include renin.
 The aspartyl endoprotease encoded by human
immunodeficiency virus catalyses essential events in
the maturation of infective virus particles.

6. Structure
 The active site of the
enzyme is C2 symmetric in
the absence of substrates
or inhibitors and contains
two essential aspartic acid
residues (Asp25 and
Asp25’). The entrance to
the active site is partly
occluded by ‘flaps’
constructed by 2 beta
strands from each
monomer, connected by a
turn. In the absence of
substrate, the flaps are
flexible.

7. Drug-Receptor Interactions
 Upon binding of inhibitors, the residues within the
flaps undergo movements upto several angstroms to
interact with the bound ligand.
 A single tightly bound water is observed in the
structures of most HIV-P-inhibitor complexes,
accepting hydrogen bonds from the backbone amides
of both flap residues and donating to carbonyls of the
bound inhibitors. This is referred to as the ‘flap’ water.
Despite the presence of this water and several tightly
bound water molecules on the floor of the active site,
the cavity also contains extensive hydrophobic surface
area.

8.  Subnanomolar inhibitor (modified octapeptide) was
used to define the extensive hydrophobic and
hydrogen bonding interactions available in the HIV-P
active site.
 The central hydroxy group of inhibitors interact with
the carboxylates of both Asp25 and Asp25’. This
hydroxyl group replaces a water molecule that likely
binds between these aspartyl side chains during
peptide hydrolysis by HIV-P.

9. History of drugs
 Alcohol diamines and diol diamines
were examined and entered clinical
trials as antiviral agent for
intravenous treatment of AIDS.
 The X-ray structure of complexes
between HIV-P and diol diamine
derivatives showed that although
one of the hydroxyl groups bound
between the catalytic aspartyl
carboxylates and made contacts
with both, the second hydroxyl
made only one such contact. Thus
the cost of desolvating the second
inhibitor hydroxyl upon binding is
not compensated by strongly
favorable interactions in the
complex.

10.  A series of cyclic ureas
were designed to interact
with both the aspartyl
carboxylates and the Ile50
and Ile50’ backbone
amides that hydrogen
bond with the flapwater.
The compounds interacted
with the HIV-P in a highly
symmetrical fashion as
they had been designed to
do so, with the urea
replacing the flap water.
 This compound showed
animal toxicity and thus
wasn’t processed further.

11. Drugs

12. Saquinavir
 It was the first HIV-P
inhibitor approved for
human use.
 Precursor of Saquinavir
comprises of proline at
one site and phenylalanine
at the other.

13. Indinavir
 Indinavir was the result
of successful application
of SBDD at Merck to
overcome the problem of
low bioavailability due to
low solubility.
 Crixivan ( the sulphate of
Indinavir) was
successfully launched for
use as an antiviral drug.

14. Amprenavir
 Amprenavir is the most
recent addition to the
HIV-P inhibitors
approved for human
antiviral treatment.
 It was designed to
minimize molecular
weight to increase oral
bioavailability.

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