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

Abstract

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.

• Authors: Steven S Good, Adel Moussa, Xiao-Jian Zhou, Keith Pietropaolo, Jean-Pierre Sommadossi
• Journal: PloS one (PLoS One) Vol. 15 Issue 1 Pg. e0227104 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 31914458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Prodrugs
• Guanosine

Topics

• Animals
• Antiviral Agents (chemistry, metabolism, pharmacokinetics, pharmacology)
• Cell Line
• Drug Discovery
• Drug Evaluation, Preclinical
• Female
• Guanosine (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)
• Haplorhini
• Hepacivirus (drug effects, genetics)
• Hepatitis C (drug therapy)
• Hepatocytes (drug effects, metabolism, virology)
• Humans
• Male
• Mice
• Prodrugs (chemistry, metabolism, pharmacokinetics, pharmacology)
• Rats