17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

RESISTANCE PATHWAY ANALYSIS OF DIKETO ACID-BASED INTEGRASE INHIBITORS ALLOWS MAPPING AND PREDICTION OF CHEMICAL PROPERTIES OF INTEGRASE INHIBITORS

Antivir Ther. 2008; 13(Suppl. 3):A17 (abstract no. 15)

A Voet¹, F Christ², M De Maeyer¹, Z Debyser² and L Vandekerckhove^3
1Laboratory of Biomolecular Modelling and BioMacS, Department of Chemistry, Katholieke Universiteit Leuven, Leuven, Belgium; ²Laboratory for Molecular Virology and Gene Therapy, Katholieke Universiteit Leuven, Leuven, Belgium; ³HIV Research Unit, University Hospital Ghent, Ghent, Belgium

BACKGROUND: Integrase inhibitor development has been hampered over the last decade by the lack of a crystal structure of the full length enzyme. Moreover, a functional pre-integration complex harbours next to an integrase tetramer or octamer, viral DNA and most probably LEDGF/p75, a cofactor of integration. Diketo acids (DKAs) bind integrase after 3′ processing of the viral DNA. Most integrase inhibitors harbour three structural components, the –CO-CO-CH2-CO- pharmacophore, a hydrophobic moiety and a fluorobenzyl side chain.

METHODS: Using the MOE modelling package, L-708,906, L-870,810, raltegravir, elvitegravir and S-1360 were complexed with the structure of an integrase catalytic core domain bound to the viral cDNA (based on the transposon 5-DNA complex structure).

RESULTS: Although resistance against DKA is mainly located in amino acids surrounding the catalytic core domain, the DKA hydrophobic group (which is oriented outside the surface upon MOE mapping) determines resistance in the β-barrel C-terminal part of integrase. As a consequence, DKAs lacking the hydrophobic group (for example, S-1360) do not select for resistance in the C-terminal part of intergrase and are not cross-resistant for these mutations. These results also indicate that the C terminus of integrase folds towards the integrase catalytic core in the functional integrase complex. The LEDGF binding side can be mapped in the dimer integrase complex and is different from the DKA binding side. The DKA fluorobenzyl ligand, which is important for antiviral activity, binds into the groove in near proximity of the D64 and D116 suggesting that this ligand locks the complex. The 5′ viral DNA is localized near the Q148, which explains why mutations in Q148 alter affinity for 5′ viral DNA.

CONCLUSIONS: The current resistance mutations against DKAs allow mapping of the strand transfer inhibitors to a model of integrase and to better understand the organization of the functional integrase complex and the different binding sides of DKAs and LEDGF/p75. S-1360 lacks the hydrophobic moiety across from the DKA pharmacophore, produces a different resistance pattern and is not sensitive to mutations in the C-terminal part of integrase. Better understanding of the integrase viral DNA-inhibitor complex is highly important for the development of new generation integrase inhibitors.

2008-06-10
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