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


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

1. Hepatitis C Fact Sheet. World Health Organization 2019 [updated Jul 9, 2019. Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-c.]

2. AASLD-IDSA. Recommendations for Testing, Managing, and Treating Hepatitis C 2019 [updated Nov 6, 2019. Available from: https://www.hcvguidelines.org/evaluate/testing-and-linkage.]

3. Feld J, Jacobson I, Sulkowski M, Poordad F, Tatsch F, Pawlotsky J. Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection. Liver Int. 2017;37(1):5–18. doi: 10.1111/liv.13212 27473533

4. Hosein S. HCV treatment in advanced liver disease CATIE2018 [Available from: https://www.catie.ca/en/treatmentupdate/treatmentupdate-227/hepatitis-c-virus/hcv-treatment-advanced-liver-disease.]

5. Migliaccio G, Tomassini J, Carroll S, Tomei L, Altamura S, Bhat B, et al. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J Biol Chem. 2003;278(49):49164–70. doi: 10.1074/jbc.M305041200 12966103

6. Ahmad T, Yin P, Saffitz J, Pockros P, Lalezari J, Shiffman M, et al. Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C. Hepatology. 2015;62(2):409–16. doi: 10.1002/hep.27488 25251156

7. Lalezari J, Nelson D, Hyland R, Lin M, Rossi S, Symonds W, et al., editors. Once-daily sofosbuvir plus ribavirin given for 12 or 24 weeks in treatment-naive patients with HCV infection: the QUANTUM study. EASL; 2013; Amsterdam, The Netherlands: Hepatology. doi: 10.1053/j.gastro.2013.11.007

8. Chang W, Bao D, Chun B-K, Naduthambi D, Nagarathnam D, Rachakonda S, et al. Discovery of PSI-353661, a novel purine nucleotide prodrug for the treatment of HCV infection. ACS Med Chem Lett. 2011;2:130–35. doi: 10.1021/ml100209f 24900291

9. Murakami E, Tolstykh T, Bao H, Niu C, Steuer H, Bao D, et al. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010;285(45):34337–47. doi: 10.1074/jbc.M110.161802 20801890

10. Murakami E, Bao H, Mosley R, Du J, Sofia M, Furman P. Adenosine deaminase-like protein 1 (ADAL1): characterization and substrate specificity in the hydrolysis of N(6)- or O(6)-substituted purine or 2-aminopurine nucleoside monophosphates. J Med Chem. 2011;54(16):5902–14. doi: 10.1021/jm200650j 21755941

11. Arnold J, Sharma S, Feng J, Ray A, Smidansky E, Kireeva M, et al. Sensitivity of mitochondrial transcription and resistance of RNA polymerase II dependent nuclear transcription to antiviral ribonucleolsides. PLoS Pathog. 2012;8(11):e1003030. doi: 10.1371/journal.ppat.1003030 23166498

12. Feng J, Xu Y, Barauskas O, Perry J, Ahmadyar S, Stepan G, et al. Role of mitochondrial RNA polymerase in the toxicity of nucleotide inhibitors of hepatitis C virus. Antimicrob Agents Chemother. 2016;60(2):806–17. doi: 10.1128/AAC.01922-15 26596942

13. Furman P, Murakami E, Niu C, Lam A, Espiritu C, Bansal S, et al. Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661. Antiviral Res. 2011;91(2):120–32. doi: 10.1016/j.antiviral.2011.05.003 21600932

14. Niu C, Tolstykh T, Bao H, Park Y, Babusis D, Lam A, et al. Metabolic activation of the anti-hepatitis C virus nucleotide prodrug PSI-352938. Antimicrob Agents Chemother. 2012;56(7):3767–75. doi: 10.1128/AAC.00530-12 22526308

15. Bonatti S, Pigullo S, Simili M, Abbondandolo A. Induction of apoptosis and inhibition of signalling pathways by alkylated purines. Mutagenesis. 2000;15(4):361–6. doi: 10.1093/mutage/15.4.361 10887217

16. Berry L, Wollenberg L, Zhao Z. Esterase activities in the blood, liver and intestine of several preclinical species and humans. Drug Metab Lett. 2009;3(2):70–7. doi: 10.2174/187231209788654081 19601867

17. Bahar F, Ohura K, Ogihara T, Imai T. Species difference of esterase expression and hydrolase activity in plasma. J Pharm Sci. 2012;101(10):3979–88. doi: 10.1002/jps.23258 22833171

18. Ahmad T, Yin P, Pockros P, Lalezari J, Shiffman M, Freilich B, et al. Cardiac dysfunction associated with a nucleotide polymerase inhibitor for threatment of hepatitis C. Hepatology. 2015;62(2):409–16. doi: 10.1002/hep.27488 25251156

19. Feng J. Addressing the selectivity and toxicity of antiviral nucleosides. Antivir Chem Chemother. 2018;26:2040206618758524. doi: 10.1177/2040206618758524 29534607

20. Bonatti S, De Ferrari M, Pisano V, Abbondandolo A. Cytogenetic effects induced by alkylated guanine in mammalian cells. Mutagenesis. 1986;1(2):99–105. doi: 10.1093/mutage/1.2.99 3333274

21. Simili M, Pellerano P, Tavosanis G, Arena G, Bonatti S, Abbondandolo A. The induction of aneuploidy by alkylated purines: effects on early and late cell cycle events. Mutagenesis. 1995;10(2):105–11. doi: 10.1093/mutage/10.2.105 7603326

22. Walsky R, Obach R. Validated assays for human cytochrome P450 activities. Drug Metab Dispos. 2004;32(6).


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