Drug Discovery
Program leader: Richard Whitley
SE-RP-015: Fusion inhibitors of H5N1 influenza
University of Alabama at Birmingham
Emerging avian influenza viruses pose an increasing threat to domestic poultry and human health. Since 2003 highly pathogenic avian influenza (HPAI) H5N1 viruses have spread to wild bird populations across Asia, Europe and Africa. These viruses have infected hundreds of humans, killing more than 50%, and may cause a global pandemic if they acquire efficient human-to-human transmissibility. The influenza virus hemagglutinin (HA) is an attractive drug target because they are essential for viral entry, and indispensable for virus replication. We hypothesize that fusion inhibitors currently under development in my lab will be potent against diverse virus strains, especially HPAI viruses, and will provide synergistic decreases in drug resistance and infectious disease when used in combination therapies. We propose the following specific aims to further develop these inhibitors:
Aim 1. Identify fusion inhibitors that are potent against diverse strains of H5N1 influenza viruses. Our preliminary studies have identified a group of lead compounds that have EC50 values in single digit nanomoles across diverse influenza virus strains including H5N3 (vaccine strain), H3N2, H1N1 and type B. To identify potential candidates for preclinical and eventual clinical studies against HPAI H5N1 viruses, we propose to develop a library of analogs based on the initial lead. We propose to measure the inhibitory potencies of candidate compounds against diverse strains of H5N1 influenza viruses.
Aim 2. Determine the mechanisms of action of HA protein inhibitors. The preliminary studies showed that the fusion inhibitors we have developed alter the structure of HA. For compounds identified in Aim 1 that are potent against H5N1 viruses, we will determine which step of virus entry is blocked using biological and biochemical assays. To map the binding sites of compounds, we will co-crystallize the HA protein with bound inhibitor. A good understanding of how compounds interact with HA protein is expected to provide fundamental insights into the membrane fusion mechanism and may lead to improvements of inhibitor design.
Aim 3. Determine if drug combinations that include HA inhibitors provide advantages over existing single-agent therapies in protecting against disease and avoiding drug resistance. A widespread use of HA inhibitors could result in the emergence of drug-resistant viruses, similar to the acquisition of drug resistance that has been observed for neuraminidase (NA) and M2 inhibitors. We hypothesize that the use of HA inhibitors in combination with existing NA and/or M2 inhibitors will help counteract drug resistance and decrease the severity of infectious disease. We propose to determine the efficacy of HA inhibitors in vitro and in vivo, alone or in combination with another inhibitor. We will study the synergy provided by combination therapy against H5N1 influenza viruses.
