Novel Low Dose Human Cytomegalovirus Inhibitor

UNMET NEED: Infection with human cytomegalovirus (HCMV) continues to be a major threat for pregnant women and immunocompromised hosts. Although anti-HCMV therapies are available, development of new agents are desired because of the limited drugs approved for HCMV, the side effects associated with them, and the emergence of resistant viral mutants during therapy.
 
TECHNICAL DETAILS: Through screening of the LOPAC library, we identified emetine as HCMV inhibitor. Studies in the JHU researchers lab revealed that the EC50 of Emetine is 40 nM and its CC50 is 8 uM, resulting is selectivity index of 200. HCMV inhibition by emetine required an interaction of  ribosomal protein 14 and MDM2. Pharmacokinetic studies performed at NIH-NCATS revealed high tissue concentrations of emetine dosed at 1 mg/kg and a long half-life (24 h). Emetine was well-tolerated in mice. Infection with mouse CMV and emetine treatment revealed high efficacy in mouse CMV inhibition even at 0.1 mg/kg administered orally every 72 h.  These in vitro and in vivo studies indicate the potential repurposing of emetine for HCMV, either alone or combined with approved HCMV drugs.
 
MAJOR RESULTS:

• Emetine is shown for the first time to inhibit HCMV replication at very low drug concentrations
• Emetine inhibits HCMV at an early stage (after entry but before DNA replication), a mechanism that is different from current HCMV inhibitors
• Emetine inhibits mouse CMV replication (in vivo) at a very low dose (0.1 mg/kg) which correlate with human dose of 0.01 mg/kg.
• HCMV inhibition by emetine involves a novel cellular pathway that requires RPS14 and its binding to MDM2.

 
INVENTORS: Ravit Boger, Marc Ferrer, Juan Marugan, Andres Garcia, Noel Southall
 
PATENT STATUS: Pending PCT Application WO 2017/120225
 
ASSOCIATED PUBLICATIONS:  PLoS Pathog. 2016 Jun 23;12(6):e1005717.

Category(s):