Use of low dose emetine for inhibition of human cytomegalovirus (HCMV)
Inventors
Boger, Ravit • Ferrer, Marc • Marugan, Juan • Garcia, Andres Dulcey • Southall, Noel Terrence • Hu, Xin
Assignees
Johns Hopkins University • US Department of Health and Human Services
Publication Number
US-12208093-B2
Publication Date
2025-01-28
Expiration Date
2037-01-04
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Abstract
The present invention relates to the field of virology. More specifically, the present invention provides methods and compositions useful for prevention and treatment of human cytomegalovirus (CMV). In one embodiment, a pharmaceutical composition comprises (a) emetine or a derivative thereof; (b) a human cytomegalovirus (HCMV) drug; and (c) a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises an adjuvant. In a specific embodiment, the HCMV drug is ganciclovir. In such embodiments, emetine is present at about 1/10 to about 1/100 the normal dosage for amebiasis.
Core Innovation
The invention provides methods and compositions useful for prevention and treatment of human cytomegalovirus (HCMV). It comprises pharmaceutical compositions including emetine or its derivatives, optionally in combination with HCMV drugs such as ganciclovir and vaccine adjuvants, administered at significantly lower doses than those used for amebiasis. The discovery is that emetine inhibits HCMV replication at very low concentrations (EC50 of 40 nM) with high selectivity and efficacy in vitro and in vivo.
The invention addresses the problem that existing HCMV therapies rely exclusively on viral DNA polymerase inhibitors, which have limited approved drugs, significant side effects, and the emergence of drug-resistant mutants during therapy. Hence, there is a pressing need for anti-HCMV compounds with novel mechanisms of action. The invention reveals that emetine acts at an early stage of viral replication after entry but before DNA replication through a novel host-dependent mechanism involving ribosomal protein S14 (RPS14) and MDM2, disrupting their interactions with viral factors.
Claims Coverage
The patent presents three main inventive features derived from independent claims related to pharmaceutical compositions and methods for treating HCMV.
Synergistic pharmaceutical composition comprising emetine and HCMV drugs
A pharmaceutical composition comprising (a) emetine; (b) a human cytomegalovirus drug selected from ganciclovir, valganciclovir, maribavir, foscarnet, and cidofovir; and (c) a pharmaceutically acceptable carrier.
Pharmaceutical composition further comprising an adjuvant
The pharmaceutical composition of emetine and an HCMV drug further comprises an adjuvant suitable for treating HCMV.
Method for treating HCMV using a synergistic combination
A method for treating HCMV in a patient comprising administering a therapeutically effective amount of emetine in combination with a human cytomegalovirus drug selected from the group consisting of ganciclovir, valganciclovir, maribavir, foscarnet, and cidofovir, wherein the combination acts synergistically.
The claims cover pharmaceutical compositions containing emetine combined with approved HCMV drugs with or without adjuvants and methods of treating HCMV in patients using these synergistic combinations.
Stated Advantages
Emetine inhibits HCMV replication at very low drug concentrations with a high selectivity index of 200.
Emetine acts through a novel host-dependent mechanism, different from existing HCMV inhibitors.
Emetine shows synergistic antiviral activity when combined with approved HCMV drugs such as ganciclovir.
Low dose emetine is well tolerated in vivo with high tissue concentrations and a long half-life.
Low dosage required for antiviral effect reduces risk of severe side effects compared to traditional amebiasis doses.
Documented Applications
Prevention and treatment of human cytomegalovirus (HCMV) infection in patients.
Combination therapy with emetine and approved HCMV drugs for enhanced antiviral efficacy.
Potential treatment of herpes simplex virus (HSV), Epstein-Barr virus (EBV), and Kaposi's Sarcoma-Associated Herpesvirus (KSHV).
Use in transplant recipients, AIDS patients, congenitally infected children, and other immunocompromised subjects.
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