ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens
| Autor: | Manohar Saindane, Debbie G. Mitchell, Prabhakar Reddy, Abel De La Rosa, Gregory R. Bluemling, Alexander A. Kolykhalov, Vindhya Edpuganti, Douglas L. Mayers, Katherine E. Squires, Zachary M. Sticher, David B. Guthrie |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Hepatitis B virus phosphoramidate 030106 microbiology Viremia Pharmacology medicine.disease_cause liver Antiviral Agents 03 medical and health sciences 0302 clinical medicine Hepatitis B Chronic clevudine medicine Adefovir Humans Pharmacology (medical) nucleoside analogs Nucleoside analogue business.industry Nucleotides Lamivudine virus diseases Entecavir medicine.disease Hepatitis B Infectious Diseases Clevudine HBV DNA Toxicity 030211 gastroenterology & hepatology prodrug business medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 1098-6596 |
| Popis: | ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5′-phosphoramidate to deliver the 5′-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5′-monophosphate is converted to the active 5′-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5′-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5′-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5′-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy. |
| Databáze: | OpenAIRE |
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