Nucleoside to treat Drug-Resistant HBV

University of Georgia Research Foundation
posted on 06/01/2010

A UGA researcher has synthesized a new nucleoside compound and evaluated its antiviral activity against wild-type HBV as well as drug-resistant mutants in vitro. Researchers also compared the antiviral activity of this compound to that of adefovir and lamivudine.

Suggested Uses

Treatment of drug-resistant HBV

Advantages

I. Anti-HBV activity against wild-type HBV with an EC50 value similar to that of adefovir, while the concentration of the nucleodie required to inhibit 90% (EC90) of HBV DNA in wild-type is a 1.5 fold more effective than that of adefovir.

II. Excellent activity against both lamivudine- and adefovir- associated HBV mutants rtN236T, rtM204V and rtM204I, and rtL180M.

III. Against double mutant rt180M/rtM204V, the compound exhibited an EC50 value equal to adefovir, while the EC90 value of the compound is more effective than that of adefovir.

IV. Recently, monophosphate prodrugs were synthesized and demonstrated >10 fold increase of potency in comparison to the parent compound against wild-type virus with an EC50 value of 0.062 µM and CC50 value of >300 µM. The evaluation of antiviral potency of the prodrug against mutants is in progress.

Innovation Details

Detailed Description

Chronic HBV infection is one of the leading causes of morbidity and mortality worldwide. Chronic infection with the hepatitis B virus (HBV) occurs in approximately 350 million people globally, including 1.2 million in the United States. HBV infection can persist for the life of the patient, often leading to severe consequences such as liver failure, fibrosis, cirrhosis, and eventually hepatocellular carcinoma.

The pivotal role of nucleoside/nucleotide analogues is undisputed. However, their long-term therapy is often associated with drug resistance, which significantly compromises the clinical application of these agents. For example, the extensive use of lamivudine resulted in the emergence of resistant mutants; 24% resistance after a 1-year of therapy increased to 70% after 4 years of therapy. Therefore, it is obvious that for the future treatment of drug resistant patients, novel anti-HBV agents, which are not cross-resistant with the current agents, are critically needed.

File Number: 1536

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