18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

NEW INTEGRASE BINDING INHIBITORS ACTING IN SYNERGY WITH RALTEGRAVIR

Antivir Ther 2009; 14 Suppl 1:A29 (abstract no. 27)

L Thibaut¹, S Rochas¹, J Dourlat¹, C Monneret¹, K Carayon², E Deprez², JF Mouscadet³, E Soma¹ and S Lebel-Binay^1
1BioAlliance Pharma, Paris, France; ²ENS, Cachan, France

BACKGROUND: HIV type-1 (HIV-1) integrase activity involves multiple steps that occur in different cell compartments, such as 3´processing in the cytoplasm and strand transfer in the nucleus. The only marketed integrase inhibitor, raltegravir (RAL), belongs to the integrase strand transfer inhibitor (INSTIs) family. We previously described a new class of integrase inhibitors, the quinoline family acting as integrase binding inhibitors (INBIs). The aim of the current study was to determine whether a synergy could occur between the two families of integrase inhibitors. Our lead, QNL111, was compared with RAL in wild-type and resistant viruses.

METHODS: Using an anisotropy fluorescence assay, the in vitro inhibition of integrase activity was studied for QNL111 and RAL. The synergism was determined between QNL111 and RAL in six viruses: a wild type (NL4.3) and the INSTIs mutants E92Q, G140S, Q148H, N155H, G140S/Q148H and E92Q/N155H. Viruses were tested with each drug alone and in combination on HeLa-P4 cells. The synergism between QNL111 and RAL was defined using the multiple drug effect principle of Chou and Talalay using the Calcusyn software (Biosoft, UK). Synergy was defined as a combination index (CI)<1, additive effect as CI=1 and antagonism as CI>1.

RESULTS: The results showed that QNL111 compound inhibited the binding of HIV-1 integrase to its substrate, whereas RAL did not. Moreover, QNL111 remained active on viruses carrying the main resistance mutations selected by RAL. The QNL111 and RAL synergism was determined at CI=0.5 ±0.12 on wild-type virus (NL4.3). For the INSTIs mutants’ viruses, the synergism was determined. The synergism occurred for all the single mutants. For the double mutants, such as E92Q/N155H and G140S/Q148H, the synergism was weaker.

CONCLUSIONS: QNL111 displayed a potent activity against integrase enzyme and HIV-1 virus replication. QNL111 prevented the binding of HIV-1 to its substrate, confirming the new mechanism of action of this new INBIs’ family. Furthermore, these results highlighted the huge potential interests of this new class of integrase inhibitors: firstly, QNL111 and RAL act in synergy on wild-type viruses and secondly, QNL111 remained active on highly RAL-resistant viruses.

2009-06-09
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