There remains a clear unmet need for filovirus-specific therapeutics. We previously identified as potential antiviral targets filoviral innate immune evasion proteins;the Ebola virus (EBOV) VP35 (eVP35) and Marburg virus (MARV) VP35 (mVP35), the EBOV VP24 and the MARV VP40 proteins. We demonstrated that eVP35 and mVP35 impair IFNapha/beta production by targeting RIG-l-like receptor (RLR) signaling pathways. We further defined the molecular, biochemical and structural bases for these inhibitory functions. Validating VP35s as therapeutic targets, we also found that EBOVs impaired for VP35 IFN-antagonist function fail to cause disease in any animal model tested. VP35 inhibitors should therefore have therapeutic benefit. We also demonstrated that the EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins inhibit Jak-STAT signaling triggered by IFN-alpha/beta and IFN-gamma, thereby blocking their antiviral effects. Further, our mVP40 data Implicate its IFN antagonist function as a virulence determinant in mice. These IFN Inhibitory functions likely contribute to the Ineffectiveness of IFNs as anti-filoviral therapies. Drugs that Inhibit eVP24 or mVP40 IFN-antagonist functions should augment the antiviral effects of therapeutically-administered IFNs or IFNs produced during the course of infection. Such inhibitors should also synergize with inhibitors of VP35 which will trigger production of IFN-alpha/beta specifically In Infected cells. Here, we capitalize on an established, highly productive collaboration (between the Basler and Amarasinghe labs) and our previous identification of these proteins as potential therapeutic targets to develop assays for high throughput screening for inhibitors of filoviral IFN-antagonist functions. The assays will be provided to Project 2, who will perform high throughput screens and identify and optimize leads. Leads identified by Project 2 will be passed to Project 1 to validate binding, determine the functional and structural basis for their action, define structure-based optimization strategies, and assess pan-filoviral potential by testing their impact on the function of IFN-antagonists from all EBOV species and MARV clades. These assessments will inform the optimization of leads through medicinal chemistry, which will be performed by Project 2.
Ebola and Marburg filoviruses cause a highly lethal hemorrhagic fever and are of concern as potential bioweapons. This project will develop inhibitors targeting the filovirus Innate Immune evasion functions as anti-Ebola and Marburg virus therapies.
|Ammosova, Tatyana; Platonov, Maxim; Ivanov, Andrei et al. (2014) 1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription. Br J Pharmacol 171:5059-75|
|Shabman, Reed S; Jabado, Omar J; Mire, Chad E et al. (2014) Deep sequencing identifies noncanonical editing of Ebola and Marburg virus RNAs in infected cells. MBio 5:e02011|
|Basler, Christopher F (2014) New hope in the search for Ebola virus treatments. Immunity 41:515-7|
|Johnson, Joshua C; Martinez, Osvaldo; Honko, Anna N et al. (2014) Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells. Antiviral Res 107:102-9|
|Xu, Wei; Edwards, Megan R; Borek, Dominika M et al. (2014) Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16:187-200|
|Kumari, Namita; Iordanskiy, Sergey; Kovalskyy, Dmytro et al. (2014) Phenyl-1-Pyridin-2yl-ethanone-based iron chelators increase I?B-? expression, modulate CDK2 and CDK9 activities, and inhibit HIV-1 transcription. Antimicrob Agents Chemother 58:6558-71|
|Basler, Christopher F; Woo, Patrick C Y (2014) Editorial overview: emerging viruses. Curr Opin Virol 5:v-vii|
|Ilinykh, Philipp A; Tigabu, Bersabeh; Ivanov, Andrey et al. (2014) Role of protein phosphatase 1 in dephosphorylation of Ebola virus VP30 protein and its targeting for the inhibition of viral transcription. J Biol Chem 289:22723-38|
|Basler, Christopher F (2014) Portrait of a killer: genome of the 2014 EBOV outbreak strain. Cell Host Microbe 16:419-21|
|Feagins, Alicia R; Basler, Christopher F (2014) The VP40 protein of Marburg virus exhibits impaired budding and increased sensitivity to human tetherin following mouse adaptation. J Virol 88:14440-50|