The potential of signal peptide peptidase as a therapeutic target for hepatitis C

Chronic infection with hepatitis C virus (HCV) causes liver steatosis, cirrhosis, metabolic syndrome with inflammation, and eventually leads to hepatocellular carcinoma. HCV core protein is a well-known capsid protein and pathogenic factor related to lipid accumulation, type 2 diabetes mellitus, and carcinogenesis. Cleavage of the C-terminal transmembrane region by signal peptide peptidase (SPP) is required for maturation of the core protein. Areas covered: Herein, this review details the general aspects of the structure, lifecycle, pathogenesis, and maturation of the HCV core protein, the function of SPP, and clinically available direct-acting antivirals (DAAs). SPP is classified into a group of GXGD-type intramembrane proteases including presenilin-1, which is a component of γ-secretase complex. Several SPP inhibitors were previously identified from γ-secretase inhibitors, but have not yet been improved based on specificity to SPP. Finally, the author discusses the potential of SPP inhibitors for hepatitis C therapy. Expert opinion: Currently available DAAs therapies are limited because of different viral genotypes and underlying conditions in each patient. DAA-resistant viruses have also been reported. Development of SPP-selective inhibitors may improve current HCV therapies by decreasing in the emergence of DAA-resistant viruses irrespective of viral genotype.