MCM-Drive-29

Small-Molecule Therapeutics against Priority Myxovirus Pathogens

July 8, 2013

The goal of this project is to develop host-directed inhibitors of myxovirus replication that are designed to transform the prevalent one-drug, one-bug approach of antiviral therapy to a one-drug, multiple-bugs paradigm. This approach aims to systemically address two major challenges frequently associated with viral therapeutics: pre-existing or rapidly developing resistance to the inhibitor, and the narrow spectrum of activity associated with the majority of antiviral drugs.

The operating hypothesis is that these obstacles can be overcome through therapeutic targeting of host cell pathways required for virus propagation, since individual viral mutations will likely not result in loss-of-function of a host pathway, and because viruses of related families frequently depend on overlapping sets of host components for completion of their life cycle.

Considering the potential for drug-induced side effects that may be associated with the host-factor approach, priority pathogens of the myxovirus families that predominantly cause acute disease, such as influenza virus, Nipah virus, Hendra virus, and mumps virus, emerge as particularly suitable first targets for this therapeutic strategy. In these cases, treatment, and thus host exposure to the drug, will be episodic and of short duration.

This Project will build on the foundation of our established anti-myxovirus program, which currently has identified molecules with nanomolar activity against influenza virus and members of the paramyxovirus family, and pursue the development of innovative small-molecule antivirals to Clinical Candidate status suitable for IND enabling studies through a combination of high-throughput screening, in silico scaffold diversification, and synthetic development of new Hits and existing Leads.