p38 MAP kinase inhibitors as therapeutics targeting ebolavirus entry

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DESCRIPTION (provided by applicant): The filoviruses, Ebola and Marburg viruses (EBOV and MARV), are emerging, enveloped, negative-sense RNA viruses and NIAID category A priority pathogens. Currently, there are no approved anti-filovirus therapeutics. Macrophages and dendritic cells (DCs) are cell types particularly important for EBOV infection in vivo. These are early targets of infection that support productive virus replication. Evidence suggests that infection of these cell types leads to aberrant responses that contribute to EBOV disease. For example, infected macrophages produce proinflammatory cytokines that may promote vascular leakage, and infected DCs may be dysregulated, impairing immune responses to infection. Therefore, therapeutics that prevent infection of these cell types or that modify their responses to infection may prove beneficial. Preliminary studies have demonstrated that small molecule compounds previously characterized as p38 MAP kinase (p38 MAPK) inhibitors impair, in primary human macrophages and DCs, entry of Zaire EBOV virus-like particles (VLPs) and inhibit Zaire EBOV replication. These data suggest that p38 MAP kinases may play an important role in EBOV entry into macrophages and DCs. They also suggest that p38 MAP kinases may be useful as anti-EBOV drugs. In addition to their ability to inhibit entry and replication, p38 inhibitors are intriguing as anti- EBOV agents because they have been developed as anti-inflammatory drugs. Therefore, they may also suppress virus-induced inflammation in vivo. In addition, some p38 inhibitors have progressed as far as human clinical trials. Therefore, there are a number of readily available p38 MAPK inhibitors; and there is a substantial literature on the toxicity, pharmacokinetics and pharmcodynamics of these compounds that could facilitate the transition from in vitro studies to proof of principle animal efficacy studies. This project wil further evaluate p38 MAP kinase inhibitors as anti-filoviral agents in vitro and in mice. It will frst define the antiviral efficacy of commercially-available p38 MAP kinase inhibitors in cell culture and in mice and determine whether the inhibition of EBOV entry and replication occurs through inhibition of p38 MAPKs. Second, it will determine the impact of p38 MAP kinase inhibitors on EBOV-induced cytokine production in cell culture and in vivo. Finally, it will test the hypothesis that p38 MAP kinases are required for macropinocytosis-mediated entry of EBOV into macrophages and dendritic cells. At its conclusion, the potential for these drugs to serve as anti- filovirus entry inhibitors and suppressors of viral inflammation will be defined; and new details o the EBOV entry pathway in macrophages and DCs will be revealed. PUBLIC HEALTH RELEVANCE: Ebolaviruses are a public health concern because they are deadly and could be used by terrorists as bioweapons. Currently there are no approved drugs to treat these infections. This project will test p38 MAP kinase inhibitors as anti-Ebolavirus drugs i cell culture and in vivo.