In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound AIC246

Abstract

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 these drugs are effective, several drawbacks are associated with their use, including toxicity and emergence of drug resistance. Hence, new and improved antivirals with novel molecular targets are urgently needed. Here we report on the antiviral properties of AIC246, a representative of a novel class of low-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 ganciclovirresistant viruses, is well tolerated in different cell types (median selectivity index, 18,000), 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.Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen in immunocompromised individuals, including transplant recipients and tumor or AIDS patients, and remains the leading viral cause of birth defects (1,9,12,17,29). To date, a limited number of drugs are licensed for the systemic treatment of HCMV infection and disease: ganciclovir (GCV) (Cymevene; Roche), its oral prodrug valganciclovir (VGCV) (Valcyte; Roche), cidofovir (CDF) (Vistide; Gilead), and foscarnet (FOS) (Foscavir; Astra-Zeneca). In addition, valaciclovir (VACV) (Valtrex; GlaxoSmithKline), a drug that has been primarily developed for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infection, has gained marketing approval in certain countries for prophylaxis of HCMV infections in transplant patients. Although GCV, VGCV, CDF, and FOS are effective, several drawbacks are associated with the use of these drugs, including toxicity, poor oral bioavailability (except VGCV), and emergence of drug resistance (3,20). The active forms of GCV, CDF, and FOS share the same molecular target, the viral polymerase UL54. Consequently, drug-resistant strains of HCMV encoding UL54 mutations have been found for all three compounds, and the emergence of cross-resistant strains has been described in clinical settings. In addition, resistance to GCV is also associate...

The Novel Anticytomegalovirus Compound AIC246 (Letermovir) Inhibits Human Cytomegalovirus Replication through a Specific Antiviral Mechanism That Involves the Viral Terminase

“…A promising new drug candidate with potential to improve HCMV therapy is the small-molecule compound AIC246, which is a representative of a new class of nonnucleoside HCMV inhibitors, the 3,4 dihydro-quinazolines (28). We have shown previously that AIC246 exhibits an outstanding anti-HCMV activity in vitro and demonstrates an antiviral profile superior to that of the commonly used polymerase inhibitors (28).…”

“…We have shown previously that AIC246 exhibits an outstanding anti-HCMV activity in vitro and demonstrates an antiviral profile superior to that of the commonly used polymerase inhibitors (28). AIC246 is one of the most potent anti-HCMV agents reported to date, with a cell culture EC 50 in the one-digit nanomolar range (ϳ5 nM) and a selectivity index exceeding 15,000 (28).…”

“…We have shown previously that AIC246 exhibits an outstanding anti-HCMV activity in vitro and demonstrates an antiviral profile superior to that of the commonly used polymerase inhibitors (28). AIC246 is one of the most potent anti-HCMV agents reported to date, with a cell culture EC 50 in the one-digit nanomolar range (ϳ5 nM) and a selectivity index exceeding 15,000 (28). Besides its excellent in vitro inhibitory activity against HCMV laboratory strains, AIC246 also (i) exhibits potent antiviral activity against clinical isolates, (ii) retains activity against virus strains resistant to currently approved antivirals, and (iii) exerts a potent in vivo efficacy in a mouse xenograft model (28).…”

Management of multidrug‐resistant viruses in the immunocompromised host

“…Letermovir (AIC246) belongs to this novel class of compounds and inhibits the replication of CMV without inhibiting the synthesis of viral DNA or proteins (Lischka et al, 2010;Goldner et al, 2011). Viral mutations leading to drug resistance map to the UL56 subunit of the viral terminase complex.…”

Antiviral treatment of cytomegalovirus infection: an update

“…The compound letermovir (known as AIC246) interacts with the viral UL56 subunit, which is involved in viral DNA processing and/or packaging [26,27]. Therefore, this compound designates a new mechanism of action.…”