Investigators at Johns Hopkins University have determined that emetine, a drug used in the past for amebiasis, is also effective against cytomegalovirus (CMV). Not only was emetine effective at an extremely low dose in tissue culture and in mice, it demonstrated a synergistic effect when combined with ganciclovir. Emetine has a novel cellular mechanism of action against CMV, which occurs at an early stage of viral replication.
While existing CMV drugs foscarnet, ganciclovir, and cidofovir effectively suppress CMV replication, they are associated with toxicities to the bone marrow and kidneys, so the investigators, led by infectious disease specialist Ravit Arav-Boger, set out to identify alternative compounds. A high-throughput screening for CMV inhibitors identified emetine. The researchers then tested doses of emetine at 0.1 mg/kg and 1 mg/kg against mouse CMV, and found that it was well-tolerated, had a long half-life, and was effective in inhibiting mouse CMV replication.
Emetine, a compound found in ipecac root, is used in a number of countries for amebic dysentery, as an emetic to induce vomiting, and as an expectorant in cough syrup. It was first described as a treatment for dysentery in 1638 by naturalists visiting Brazil. In 1858 it was used in India to reduce deaths from severe dysentery. In the 1960’s, parents were encouraged to keep “syrup of ipecac“ in their homes to make their children vomit after swallowing poison. Although the syrup was FDA approved for over-the-counter use in 1965, a subsequent US government review in 2005 concluded that emetine was not effective for poisoning and many times did not induce vomiting.
The investigators found that emetine inhibits CMV through a different mechanism than ganciclovir, which targets the viral DNA polymerase. Emetine inhibits CMV during the immediate-early to early stages of virus replication. A key observation was that emetine was active against CMV in high density cells but not in low density cells. This finding suggested anti-CMV activity that is cell-cycle dependent. The investigators found that in high-density infected cells, emetine induced nuclear translocation of ribosomal protein 14 (RPS14), leading to the binding of RPS14 and MDM2 and the disruption of interactions between MDM2-p53 and MDM2-viral IE2. The binding of RPS14-MDM2 resulted in the ubiquitination and degradation of RPS14.
In low-density infected cells, as well as in high-density RPS14 knockdown cells (sh-RPS14), the MDM2-p53 interaction was uninterrupted, facilitating virus replication. The investigators conclude that binding of RPS14 to MDM2 is required for emetine to successfully inhibit CMV.
CMV belongs to the beta herpesvirus family, which also includes HHV-6A, HHV-6B and HHV-7. CMV infects between 50 and 80% of adults in the United States by the age of 40 and often reactivates in transplant recipients and patients with AIDS. It is the most common congenital infection worldwide. All three FDA approved drugs for CMV are also effective against HHV-6.
For more information, see Mukhopadhyay 2016.