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A peptide inhibitor of HIV-1 protease using α, β- dehydro residues : A structure based computer model

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Title A peptide inhibitor of HIV-1 protease using α, β- dehydro residues : A structure based computer model
 
Creator Siddiqui, Mohd. Imran
Kataria, Sarika
Ahuja, Vivek
Rao, Gita Subba
 
Description 90-95
HIV-1 encodes an aspartic protease, an
enzyme crucial to viral maturation and infectivity. It is responsible forth
cleavage of various protein precursors into viral proteins. Inhibition or this
enzyme prevents the formation of mature, infective viral particles and
therefore, it is a potential target for therapeutic intervention following
infection. Several drugs that inhibit the action of this enzyme have been
discovered. These include peptidomimetic inhibitors such as ABT-538 and
saquinavir, and structure based inhibitors such as indinavir and nelfinavir.
Several of these have been tested in human clinical trials and have
demonstrated significant reduction in viral load. However, most of them have
been found to be or limited clinical utility because of their poor pharmacological
properties and also because the viral protease becomes rapidly resistant to
these drugs on account or mutations in the enzyme. One way to overcome these
limitations is to design an inhibitor that interacts mainly with the conserved
residues of HIV-1 protease. By a rational drug design approach based on the
high resolution X-ray crystal structure of the HIV-1 protease with - MVT 101 (a
substrate based inhibitor) and the specific design principles of peptides
containing dehydro-Alanine (ΔAla) derived from our earlier studies, we have
designed a tetrapeptide with the sequence: NH2-Thr –Δ Ala-ΔAla- Gln-COOH.
Energy minimization and molecular modelling of the interaction of the designed
tetrapeptide with the inhibitor binding site indicate that the inhibitor is in
an extended conformation and makes excessive contacts with the viral enzyme at
the interface between the protein subunits. The designed inhibitor has 33% of
its interaction with the conserved region of HIV-1 protease which is of the
same order as that of MVT 101 with the enzyme.
 
Date 2013-07-16T06:26:51Z
2013-07-16T06:26:51Z
2001-04
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://hdl.handle.net/123456789/19805
 
Language en_US
 
Rights CC Attribution-Noncommercial-No Derivative Works 2.5 India
 
Publisher NISCAIR-CSIR, India
 
Source IJBB Vol.38(1-2) [February-April 2001]