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Albany 2001

category image Biomolecular
Stereodynamics
SUNY at Albany
June 19-23, 2001

A Novel Peptide Inhibitor of HIV-1 Integrase: A Structure-Based Computer Model

The insertion of viral DNA into the host chromosome is an essential step in the replication cycle of HIV-1, and is carried out by an enzyme, HIV-1 integrase (IN). Since the latter has no human cellular counterpart, it is an attractive target for antiviral drug design. Several IN inhibitors, all having activities in the micromolar range have been reported to date. However, no clinically useful inhibitors have yet been developed. The X-ray crystal structure of the IN catalytic domain complexed with a non-peptidic inhibitor, 5CITEP, has recently been determined . Based on the crystal structure, we have modelled the complex of IN with a known hexapeptide inhibitor (HCKFWW) so as to identify the enzyme binding pocket of the peptide.

In the quest for new and improved small molecule inhibitors, we present here a novel approach to peptide inhibitor design, using alpha, beta unsaturated (dehydro-) amino acids, which confer a unique conformation on a peptide sequence. Based on the above models and the folding rules for peptides containing dehydro-Phe, we have selected a tetrapeptide inhibitor which is found to have an open conformation as ascertained from its X-ray crystal structure.

Molecular modeling of the complex of IN with the tetrapeptide shows that the inhibitor has contacts with the catalytic residues of IN, as well as with most of the residues that are critical for binding viral DNA substrate. We therefore expect the tetrapeptide to be an effective inhibitor of HIV-1 integrase.

Gita Subba Rao, Vivek Ahuja and Sonika Bhatnagar

Dep./Biophysics, All India Institute of Medical Sciences, New Delhi - 110029, India email: gitarao@medinst.ernet.in; Fax: 91-11-6862663; Phone: 91-11-6594816