In vitro and in vivo Activities of the novel Anti-Cytomegalovirus Compound AIC246.

Antimicrobial agents and chemotherapy 2010 Jan 4; In press

Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, Ruebsamen-Schaeff H, Zimmermann H

AiCuris GmbH & Co. KG, Friedrich Ebert-Str.475, 42117 Wuppertal, Germany.

Human Cytomegalovirus (HCMV) remains a serious threat for immunocompromised individuals including transplant recipients and newborns. To date, all drugs licensed for the treatment of HCMV infection and disease target the viral DNA-polymerase. Although effective, several drawbacks are associated with the use of these drugs including toxicity and emergence of drug resistance. Hence, new and improved antivirals with novel molecular targets are urgently needed. Here we report on the anti-viral properties of AIC246, a representative of a novel class of small molecular weight compounds that is currently undergoing clinical phase II studies. The anti-HCMV activity of AIC246 was evaluated in vitro and in vivo using various cell culture assays and an engineered mouse xenograft model. In addition antiviral properties of the drug were characterized in comparison to the current gold standard ganciclovir. We demonstrate that AIC246 exhibits excellent in vitro inhibitory activity against HCMV laboratory-strains and clinical isolates, retains activity against ganciclovir resistant viruses, is well tolerated in different cell types (median selectivity index: 18000) and exerts a potent in vivo efficacy in a mouse xenograft model. Moreover, we show that the antiviral block induced by AIC246 is reversible and the efficacy of the drug is not significantly affected by cell culture variations such as cell type or multiplicity of infection. Finally, initial mode of action analyses reveal that AIC246 targets a process in the viral replication cycle that occurs later than DNA synthesis. Thus AIC246 acts via a mode of action that differs from that of polymerase inhibitors like ganciclovir.

Keywords: Cytomegalovirus AIC246