Drugs work together with vaccines to protect us against disease. Drugs are particularly effective for short to mid-term protection or when people are in areas where a recent outbreak has occurred or vaccination is not possible. All drugs work by disrupting the function of proteins or related process. Most anti-viral drugs target virus proteins but can still suffer from side-effects where host proteins are also affected. Instead, targeting host proteins that the virus uses to infect cells, offers many more targets for treating disease. The work in my lab uses cell biology techniques to identify host proteins needed for virus infection and then to identify drugs that block the function of these proteins without harming the host. We also take a more traditional approach to identifying drug candidates by screening large chemical libraries. Toward this goal we have developed high-throughput screening platforms that work in the high containment lab setting.
Using our drug discovery pipeline we have identified small molecules that block distinct steps in Ebolavirus entry into cells. The stage at which each compound works has been carefully mapped using high resolution microscopy methods as well as biochemical and molecular biology approaches. Our microscopy work is more than just pretty pictures. We have spent a lot of time and effort in developing analysis techniques that allow quantitative information to be extracted from the images. This has allowed us to better understand which virus proteins interact with specific cell proteins by both amount and over time after virus infection. These observations are then followed up with biochemical and molecular assays to further study the interactions of the proteins. Using these techniques we have made important and novel findings about Ebolavirus, Lassa fever virus and Crimean Congo Hemorrhagic fever virus infection mechanism and have identified chemical probes to better understand the infection process and basic cell biology as well as potential therapeutics for disease treatment.
Main technologies and methods used:
- Quantitative confocal and conventional light microscopy
- siRNA and drug screening by high throughput screening and detailed follow up work
- Biochemical analysis of mechanism of action of siRNA and drugs
- Pseudotype-based assay systems for detecting virus entry inhibitors
- Virus-like particles as mimics of virus particle interaction with cells
- Sakurai Y, Sakakibara N, Toyama M, Baba M, Davey RA. Novel amodiaquine derivatives potently inhibit Ebola virus infection. Antiviral Res. In press.
- Lindstrom A, Anantpadma M., Davey RA, Davisson, JV. 2018. Phenotypic Prioritization of Diphyllin Derivatives that Block Filo-viral Cell Entry by Vacuolar (H+)-ATPase Inhibition. ChemMedChem. Oct. 18. [Epub ahead of print]. PMID: 30335906
- Luthra P, Naidoo J, Pietzsch CA, De S, Khadka S, Anantpadma M, Williams CG, Edwards MR, Davey RA, Bukreyev A, Ready JM, Basler CF. 2018. Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses. Antiviral Res. 158:288-302. PMID: 30144461.