The hepatitis C virus (HCV) infects more than 2% of the global population and an estimated 4 million individuals in the United States. The economic burden associated with HCV in the United States makes it a critical public health priority. Current therapeutics for HCV are not particularly effective and can cause severe side effects. To date, no vaccine against HCV has been developed due to the genetic diversity of the virus, however;recently antibodies that neutralize the virus'infectivity have been discovered. The discovery of these antibodies has also led to locating a well conserved binding site on HCV that blocks its entry into human cells. While antibodies are important biological proteins, they are not ideal drug candidates, due to their large complicated structure the expense associated with their synthesis, and unfavorable immune responses. In addition, as larger biological proteins, they are poor drug candidates as they are sensitive to degradation. We propose to synthesize a series peptide scaffolds that either bind to or mimic conserved sites on HCV. Using chemical means, we will develop stabilized peptide scaffolds that show high affinity to its targets. The peptides that mimic the HCV antigen sites will be used as a target for phage display. We will take advantage of the phage display library of small, stabilized mini-proteins at the laboratory of Dr. Sidhu to find possible antiviral proteins. In parallel, mirror-image phage display will also be tested as D-proteins are known to have significantly better pharmacokinetic properties.
There are almost 4 million people infected with hepatitis C (HCV) in the United States and 12,000 die annually from HCV-related liver disease. Currently there are no vaccines against HCV due to its tremendous genetic diversity. A few highly conserved regions of HCV have been identified and we propose to assemble small peptide and protein scaffolds that bind to these sites in the hopes of developing potent antivirals.
|Assem, Naila; Ferreira, David J; Wolan, Dennis W et al. (2015) Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling. Angew Chem Int Ed Engl 54:8665-8|