Anti-hepatitis Screening Libraries

Hepatitis C virus (HCV) is a leading cause of liver‐related morbidity and mortality worldwide. Hepatitis B and C cause together up to 80 % of all liver cancer deaths (close to 1.4 million fatalities per year) [1]. HCV is known as one of the most dangerous diseases requiring very expensive treatment [2]. Although there are vaccines for hepatitis A and B, there is so far no vaccine capable of protecting against viral hepatitis C as its development presents various challenges [3]. Moreover, currently available direct-acting antivirals (DAAs) against HCV are not effective against all genotypic variants of the virus, and resistance against drugs in clinical use will ultimately emerge [4]. The search for new antiviral drugs for hepatitis C treatment remains a constant challenge until its elimination would be possible.

To address this problem, Life Chemicals has designed its Anti-HCV Library using a 2D fingerprint similarity search. A reference database of 12,000 biologically active compounds (IC50, Ki, etc. <= 10 μM, inhibition > 25 %) with confirmed potency in 2,175 HCV assays was compiled (based on ChEMBL Assay data), using the data available from patents and literature publications. These compounds show activities against the following Hepatitis C virus genotypes and its targets

  • Hepatitis C virus
  • Hepatitis C virus genotype 1a (isolate 1)
  • Hepatitis C virus genotype 1b (isolate BK)
  • NS3 protease/helicase
  • NS3/NS4A serine protease
  • RNA-directed RNA polymerase
  • NS5B RNA-dependent RNA polymerase
  • Genome polyprotein

The Life Chemicals HTS Compound Collection was searched for small molecules similar to compounds from the reference database, using MDL public keys and the Tanimoto similarity cut-off of 85 %. This search resulted in a selection of almost 1,400 drug-like screening compounds of potential hepatitis C virus inhibitors.

In addition to that, Life Chemicals has prepared a small subset (204 small-molecule compounds) against Hepatitis A and B virus based on a reference database of 3,100 biologically active compounds with confirmed potency in 678 HCV assays, according to the ChEMBL database.

References:

  1. Ringelhan M, McKeating JA, Protzer U. Correction to 'Viral hepatitis and liver cancer'. Philos Trans R Soc Lond B Biol Sci. 2018;373(1737):20170339.
  2. Sylvestre D. Hepatitis C for addiction professionals. Addict Sci Clin Pract. 2007;4(1):34-41.
  3. Halliday J, Klenerman P, Barnes E. Vaccination for hepatitis C virus: closing in on an evasive target. Expert Rev Vaccines. 2011;10(5):659-672. doi:10.1586/erv.11.55
  4. Li Z, Chen ZW, Li H, Ren H, Hu P. Prevalence of hepatitis C virus-resistant association substitutions to direct-acting antiviral agents in treatment-naïve hepatitis C genotype 1b-infected patients in western China. Infect Drug Resist. 2017;10:377-392.