Development of multifunctional prodrugs for combination therapy against hepatocellular carcinoma and HCV

• Grant number: 15/23244-8
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): April 01, 2016
• Effective date (End): February 29, 2020
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Eduardo Maffud Cilli
• Grantee: Paulo Ricardo da Silva Sanches
• Home Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara, SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of death worldwide. Alcohol and viral infections are the leading causes of this disease. About 90% of HCC cases are attributed to infection by Hepatitis B and C. Unlike HBV, there is still no vaccine capable of preventing infection by HCV. Most of therapeutic agents (anti-tumor and antiviral) in use is generally not specific for affected cells and the virus, causing side effects. The drug combination and development of prodrugs have been shown to be effective in the treatment of infections and tumors, opening up new opportunities for the development of more potent and less aggressive compounds to the healthy cells. The aim of this work is to develop prodrugs that are able to internalize and deliver drugs with different mechanisms of action, and targets (antitumor and antiviral), in order to develop a combined therapy against HCV and hepatocellular carcinoma. We intend to combine the antitumor curcumin and the indole derivative 3- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydrocyclopentaindole-2-carboxylic acid and the antiviral ribavirin in a single structure (prodrugs ) containing the galactose binding specificity to promote greater tumor cells. Peptide sequences containing the cleavage site of the lysosomal enzyme cathepsin B and the viral NS3 protease / NS4A are also used to verify the release of the drug. The synthesis of these compounds will be performed by SPPS with purification and characterization by HPLC and LC-MS, respectively. Serum stability assays, release of the drug, cell viability by MTT, flow cytometry, luciferase assays, Western blotting and quantification of viral load by real-time PCR will provide results that bear relevance of these new molecules to intervene in cell proliferation of liver cancer and HCV infection