13th International HIV Drug Resistance Workshop


8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain


A MOLECULAR MODEL OF HIV-1 INTEGRASE INHIBITOR RESISTANCE

Antiviral Therapy 2004; 9:S5 (abstract 1)

D Hazuda and the Merck HIV-1 Integrase Discovery Team
Merck Research Labs, West Point, Pa., USA

This study was designed to understand the potential for cross resistance between structurally diverse inhibitors of HIV-1 integrase. We have previously shown that inhibitors of integrase strand transfer such as the 1,3 diketones (diketo acids or DKAs) and napthyridines, share a common mechanism of action in which the critical pharmacophore is involved in sequestering divalent metal ions in the active site. This is consistent with the observation that mutations associated with diketo acid resistance mapped to residues 66, 151, 153, 154 and 155, which are proximal to the active site residues that coordinate divalent metal. We have now generated viruses that are resistant to a potent inhibitor from the napthyridine class (L- 870810). These viruses contain an entirely new constellation of mutations at positions 74, 121 and 125. In studies using recombinant viruses, these mutations engender a significant loss of susceptibility to the napthyridine but do not affect activity of the DKAs. Conversely, with the exception of 155, mutations associated with resistance to the DKAs do not engender napthyridine resistance. Like the DKA mutations, the napthyridine mutations also localize to the integrase active site, however, residues associated with DKA and napthyridine resistance map to discrete regions of the active site and define remarkably distinct ligand binding surfaces, which extend in opposing directions distal to the metal binding residues. This observation together with molecular modelling studies of these inhibitors suggest a molecular basis for their discordant resistance profiles, and the role of N155 in mediating cross class resistance and maintaining the architecture of the integrase active site. The proposed model also provides a rationale for developing integrase inhibitors with complementary resistance profiles.

PRESENTING AUTHOR: D Hazuda

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2004-06-08
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