AEGiS-15IAC: Protein epitope mimetics selectively targeting HIV-1 fusion events via the cellular coreceptor CXCR4.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Protein epitope mimetics selectively targeting HIV-1 fusion events via the cellular coreceptor CXCR4.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1307)

Klimkait T, Hamy F, Brondani V, DeMarco S, Mukherjee R, Romagnoli B, Robinson JA, Gombert FO, Lociuro S, Moehle K, Vrijbloed JW, Zumbrunn J, Obrecht D
InPheno AG, Basel, Switzerland

BACKGROUND: In current HAART therapy of HIV disease most clinically available inhibitors target the viral enzymes PR and RT. However, emerging therapy resistances have created a high need for new drug discovery for alternative inhibitor classes and novel antiviral targets complementing and possibly substituting current modalities.

METHODS: We used a cellular entry screening system and human cell systems for selectively interrogating aspects of membrane fusion, viral gene transactivation, virus production, and cytotoxicity. In acute infections of human leukocytes we investigated inhibitor potency on different virus subtypes, drug resistant variants and CXCR4- and CCR5 tropic virus.

RESULTS: Protein epitope mimetics were designed as coreceptor-interfering compounds. Three anti-X4-candidates with high serum stability and antiviral potency were chosen for antiviral profiling demonstrating excellent antiviral potency in fusion-based infections with IC50 below 10nM. In extended infection with cladeB-based infections of hu-PBL they blocked HIV-1 at below 30nM (IC90). Cytotoxicity was not observed up to the highest tested concentration of 100 microM. As an "in-vitro clinical micro-study" we engineered various recombinant viruses carrying Env genes from ten randomly chosen clinical samples. Antiviral activity of compounds, e.g. POL2438, was compared to that of the fusion inhibitor T-20 used in the clinics. In contrast to high variability among variants' sensitivities to T-20 (range of >20 fold), the sensitivity to POL2438 was identical (10nM ± 1.5) on all isolates. Two viruses were not inhibited even at 100fold higher concentration. Subsequent genotypic analysis of coreceptor tropism revealed that these contained solely R5-tropic virus. POL2438 reflects a highly attractive compound with a promising antiviral profile regarding activity and selectivity towards CXCR4-tropic viruses and justifies further profiling and development. Preliminary animal data suggest a favorable in vivo toxicity profile; PK studies are currently underway.

Keywords: AEGIS, Receptors, CXCR4, HIV-1, Receptors, CCR5, HIV Infections, Anti-HIV Agents, Epitopes, Membrane Fusion, HIV Fusion Inhibitors, Genes, env, Antiviral Agents, Humans, immunology, genetics

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