The viral Achilles heel: The Nucleocapsid protein of FIV/HIV and related lentiviruses as a therapeutic target

Abstract

Therapeutic resistance to anti-viral drugs via mutation is a major challenge affecting both human and veterinary medicine. Since the discovery of the Human Immunodeficiency Virus (HIV) in 1984 this single disease has caused 25 million deaths worldwide, clearly highlighting the unique challenge in this research area. Amongst non-human vertebrates, Feline Immunodeficiency Virus (FIV) infection is perhaps the closest biological model of HIV infection with an analogous late-stage AIDS-type progression. FIV infection primarily occurs through biting and during mating with about 44 million cats currently infected worldwide. FIV and HIV are closely related to other lentiviruses including Simian Immunodeficiency Virus (SIV) and Equine Infectious Anemia Virus (EIAV), each of which is a species-specific virus using analogous proteins in the viral life cycle. The exploiting of these overlaps by targeting the mutation resistant nucleocapsid protein (NCp) in FIV that performs the same role as the NCp7 protein in HIV and other lentiviruses. This has led to the development of highly active small molecules, representing a new therapeutic approach against HIV. There is currently no crystal structure for the FIV nucleocapsid protein so, through the design of a strong homology model, we were able to dock existing and potential compounds in a form of in-silico screening using our results and the literature to train the model and improve the results. The active compounds were then synthesized and tested against chronically infected FIV cell lines, with pre-screen cytotoxic testing to assess the therapeutic window of activity. The validated anti-viral activity of the compounds puts us in a strong position for further development and the results of our approach will be described