Furopyrimidines as novel inhibitors of henipaviruses

The emergence and reemergence of pathogenic viruses represent continuous infectious disease threats
to public health. Among these, the paramyxoviruses, which include many important human and animal
pathogens, also include two excellent examples of emerged, zoonotic viral pathogens of importance: the
henipaviruses; Hendra virus (HeV) and Nipah virus (NiV). HeV and NiV have a uniquely broad host
tropism capable of infecting at least 18 animal species across 6 orders of mammals. HeV and NiV can
also cause a systemic and often fatal respiratory and/or neurological disease in 11 mammalian species
including humans. These henipaviruses remain significant biothreats to humans and economically
important livestock in Australia and throughout South East Asia. In addition, there are no vaccines or
antivirals approved for human use. Thus new treatment options are urgently needed. This application
defines a plan to develop potent, small molecule inhibitors, which inhibit henipavirus replication. We have
identified compounds that inhibit replication of these viruses, with IC50 values in the nanomolar range.
In this application, we propose three specific aims: (1) To optimize the lead (and backup) scaffold and
select developmental candidates; (2) Develop the SAR in the henipavirus infectious assay and further
investigate the mechanism of action (MOA) of the replication inhibitors; and (3) Select henipavirus
inhibitors with in vitro ADME properties suitable for whole animal testing in an infectious animal model.Project Narrative
This project is to discover and develop small molecule inhibitors for henipavirus infection.
The proposed research will help to develop potential antiviral therapeutics.