RAPID: In vitro and in vivo evaluation of CANDO predictions for Ebola virus therapeutics

University Of Washington, Seattle WA

Investigators

Abstract

There are no small molecules known to target specifically the components of Ebola virion, and therefore no effective small-molecule therapeutics approved to treat Ebola virus disease (EVD) in human patients. Even if safe drug candidates were available, there are formidable engineering and social challenges in manufacturing sufficient doses in time to make an immediate epidemiological impact. A critical advance would be to identify an already-approved and manufactured compound that could be repurposed to treat EVD. This project, if successful, will serve as a proof of concept for using powerful high-performance computing and in vivo validation for swift identification and testing of compounds that are already approved and available for human use. The PI recently developed a mouse model of Ebola virus disease using the Collaborative Cross mouse resource, which is genetically diverse yet tractable, and was shown to reproduce the range of disease outcomes observed in human EVD patients. This model will be utilized to evaluate small molecules, which have been already identified computationally by the Computational Analysis of Novel Drug Opportunities (CANDO) platform. CANDO is a novel high-performance computing approach, which docks in a massively parallel fashion all the approved drugs onto the known three-dimensional structures of target Ebola virus proteins and identifies those molecules that are most likely to bind tightly and specifically to virus proteins. Far from being limited to the pharmaceutical development field, this approach will have general applicability for rapid prediction and validation of molecular probes specific to any macromolecule with the known spatial structure. Identifying drugs that are already FDA-approved for the treatment of other conditions, but which also have activity against Ebola virus, will significantly augment efforts to control Ebola outbreaks, as this will allow us to rapidly deploy effective treatments. This will eliminate the need for costly, slow trials and reduce the risk of such drugs producing unwanted toxicity, since they have already undergone extensive testing for safety and pharmacologic characterization. This drug-repurposing approach can be applied to swiftly counter other emerging viruses for which there are no vaccines or effective treatments. The same methods, furthermore, can be directly applied to develop chemical probes that can target any large molecule with a known structure.