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21 Feb 2013

Evaluation of Phosphatidylinositol-4-kinase III as a Hepatitis C Virus Drug Target

Evaluation of Phosphatidylinositol-4-kinase IIIα as a Hepatitis C Virus Drug Target

Approximately 2.4% of the human population, corresponding to approximately 160 million individuals is infected with the hepatitis C virus (HCV). The majority of which are chronically infected with the virus which results in serious liver diseases such as cirrhosis and hepatocellular carcinoma (cancer of the liver).

The current gold standard drug therapy inhibits one of the HCV proteases known as the NS3-4A  serine protease which is essential for viral replication. This gold standard of care shows limited efficacy, particularly among patients that previously failed to respond to other treatments due to drug resistance. Research into more effective antiviral therapies has focused on host targets that may lead to broadly active drugs with pan-genotype activity (antiviral activity against all HCV genotypes), which will hopefully provide a greater barrier against drug resistance.

Several groups have independently identified phosphatidylinositol-4-kinase IIIα (PI4KIIIα) as a common target required for HCV infection and replication. It has been proposed that the host PI4KIIIα is recruited by non-structural 5A (NS5A) protein on HCV to aid with viral replication. Targeted inhibition of PI4KIIIα could potentially offer more broadly effective anti-HCV therapies.

Cambridge Research Biochemicals (CRB) raised a custom polyclonal antibody generated to a peptide sequence corresponding to amino acid residues 966-983 from the human phosphatidylinositol-4-kinase IIIα (PI4KIIIα), also conserved in mouse. The affinity purified antibody was used  in Western blotting studies to evaluate PI4KIIIα protein levels in the liver, stomach, ileum, heart and brain. Reference: Frédéric H. Vaillancourt (Boehringer Ingelheim (Canada) Ltd, Laval, Quebec, Canada, et al. November 2012. Evaluation of Phosphatidylinositol-4-Kinase IIIα as a Hepatitis C Virus Drug Target.  J. Virol. 86: 11595-11607.

The study findings suggest that lipid kinase inhibitors could be useful for treatment of many infectious diseases, in cases where the enzyme required by the infectious agent is not necessary for host function. However, PI4KIIIα plays an essential role in the host physiology, raising doubt on the pursuit of PI4KIIIα inhibitors for treatment of chronic HCV infection

Raising a custom peptide polyclonal antibody at Cambridge Research Biochemicals involves several critical steps:

  1. Synthesis of the peptide – CRB manufacture peptides at its own premises to the highest quality, turnaround 3- 4 weeks.
  2. Conjugation – Peptide is chemically conjugated to a carrier protein to help illicit an immune response.
  3. Screening – ELISA analysis is performed to monitor      antibody titre against the target of interest.
  4. Affinity purification – Peptide is chemically ligated to a sepharose resin to obtain the target antibodies of interest.

Request a quotation for custom antibody production from Cambridge Research Biochemicals.