Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus

English version

Autoři: Steven S. Good ^aff001; Adel Moussa ^aff001; Xiao-Jian Zhou ^aff001; Keith Pietropaolo ^aff001; Jean-Pierre Sommadossi ^aff001
Působiště autorů: Atea Pharmaceuticals, Inc., Boston, Massachusetts, United States of America ^aff001
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0227104

Souhrn

Despite the availability of highly effective direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal for difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior treatment experience, warranting development of more potent HCV replication antivirals. AT-527 is the hemi-sulfate salt of AT-511, a novel phosphoramidate prodrug of 2’-fluoro-2’-C-methylguanosine-5'-monophosphate that has potent in vitro activity against HCV. The EC₅₀ of AT-511, determined using HCV laboratory strains and clinical isolates with genotypes 1–5, ranged from 5–28 nM. The active 5'-triphosphate metabolite, AT-9010, specifically inhibited the HCV RNA-dependent RNA polymerase. AT-511 did not inhibit the replication of other selected RNA or DNA viruses in vitro. AT-511 was approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV genotypes 1–5 and remained fully active against S282T resistance-associated variants, with up to 58-fold more potency than SOF. In vitro, AT-511 did not inhibit human DNA polymerases or elicit cytotoxicity or mitochondrial toxicity at concentrations up to 100 μM. Unlike the other potent guanosine analogs PSI-938 and PSI-661, no mutagenic O⁶-alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC₅₀ values ≥25 μM against a panel of CYP enzymes. In hepatocytes from multiple species, the active triphosphate was the predominant metabolite produced from the prodrug, with a half-life of 10 h in human hepatocytes. When given orally to rats and monkeys, AT-527 preferentially delivered high levels of AT-9010 in the liver in vivo. These favorable preclinical attributes support the ongoing clinical development of AT-527 and suggest that, when used in combination with an HCV DAA from a different class, AT-527 may increase SVR rates, especially for difficult-to-treat patient populations, and could potentially shorten treatment duration for all patients.

Klíčová slova:

Drug metabolism – Hepatitis C virus – Mitochondria – Toxicity – Metabolites – Monkeys – Hepatocytes – Oral administration

Zdroje

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Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus

Souhrn

Klíčová slova:

Zdroje

PLOS One

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