Development of novel antiviral drugs to combat human pathogenic arenaviruses

Arenaviruses merit significant attention both as powerful models to study viral pathogenesis and as important human pathogens. Lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse, represents a powerful experimental system that provided novel concepts in immunology and virology that have been extended to other viruses, bacteria, and parasites. With over 200, 000 infections per year and several thousand deaths, Lassa virus (LFV) is by far the most important among the human pathogenic arenaviruses and represents a severe threat for human health. There are no licensed arenavirus vaccines and the current therapies are not optimal. Therefore, it is important to develop better antiviral drugs to combat the threats of arenavirus infections. A fundamental reason for the high mortality of infections with human pathogenic arenaviruses is a failure of the host’s immune system to control viral replication, leading to an unchecked viremia associated with hemorrhagic disease. Since rapid dissemination of the virus critically depends on attachment and entry into host cells, drugs targeting these steps will give the host’s immune system a wider window of opportunity for the generation of an efficient anti-viral immune response. The goal of my research was therefore the development of novel anti-viral drugs that are able to block these initial steps of infection. In a first approach to identify such “gatekeeper” drugs I performed high-throughput small molecule screening using combinatorial chemical libraries, which represent a powerful technology for discovery of specific inhibitors of receptor-ligand interactions. In a collaborative effort with the laboratory of Dr. Dale Boger (Department of Chemistry, Scripps) I used a high-throughput screening assay for inhibitors of LFV infection using retroviral pseudotypes containing LFVGP in their envelope and a luciferase reporter gene. My screening identified several small molecule compounds that show specific blocking of LFV infection in several human and primate cell types with IC50 values in the range of 1-10 µM. Some of the candidates were also active against retroviral pseudotypes the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito. In a second approach, I evaluated the activity of anionic polymers like heparin, dextrane sulfate, and fucoidan, previously shown to have anti-viral effects, against human pathogenic arenaviruses. In contrast to published data, I found no signif