There are approximately 71 million people globally who are chronically infected with the hepatitis C virus (HCV). The chronic infection of HCV may result in cirrhosis, hepatocellular carcinoma, or liver failure. AT-527 is a novel liver-targeted nucleotide prodrug for chronic HCV infection research.

AT-527 is a potent and orally active HCV viral replication inhibitor.

This inhibitor is a hemisulfate salt of AT-511, a guanosine nucleotide prodrug. AT-511 has pan-genotypic antiviral activities. It inhibits HCV genotype 1a (HCV GT1a), HCV GT1b, HCV GT2a, HCV GT3a, HCV GT4a, and HCV GT5a replication. The EC50 values of these genotypes are 12.8 nM, 12.5 nM, 9.2 nM, 10.3 nM, 14.7 nM, and 28.5 nM, respectively.

Additionally, AT-511 is approximately 10-fold more active than sofosbuvir against a panel of clinical isolates of HCV genotypes 1-5.

When given orally to rats (500 mg/kg) and monkeys (30 mg/kg, 100 mg/kg, or 300 mg/kg), AT-527 preferentially delivers high levels of AT-9010 in the liver in vivo. In rat, after a single dose by 500mg/kg, the C_max is 0.12 nmol/mL. Additionally, the T_max, AUC_0-last, and MRT_0-last are 0.29h, 0.10 nmol*h/mL, and 1.30 h, respectively. In monkeys, after a single dose of 300 mg/kg, the C_max is 0.31 nmol/mL. Additionally, the T_max, AUC_0-last, and MRT_0-last are 17.3 h, 12.2 nmol*h/mL, and 27.9 h, respectively.

AT-527 is a double prodrug of a guanosine nucleotide analog.

It possesses a unique structural feature on its nucleobase, with an N6-methyl group.  As a result, this critically differentiates it from these previously guanosine nucleotides with respect to metabolic stability.

Besides, it is highly efficacious and well-tolerated in HCV- infected subjects. What’s more, the free base form of AT-527, AT-511 is against several coronaviruses, including SARS-CoV-2. And we all know, SARS-CoV-2 is the causative agent of COVID-19. In normal human airway epithelial cells, the concentration of AT-511 to inhibit replication of SARS-CoV-2 by EC₉₀ is 0.47 μM. This EC₉₀ is very similar to its EC₉₀ against HCoV-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells.

In summary, AT-527 has pan-genotypic antiviral activity. This compound can be used for HCV or SARS-CoV-2  infection in vitro and in vivo.

Reference:

[1]. Steven S Good, et al. PLoS One. 2020 Jan 8;15(1):e0227104.

[2]. Steven S Good, et al. Antimicrob Agents Chemother. 2021 Feb 8;AAC.02479-20.