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Abstract

Viral hemorrhagic fevers (VHF) are a group of viral illnesses that are characterized by a loss of homeostatic control. VHF is associated with a collapse of the integrity of the vascular system leading to increased bleeding tendency and shock. VHF?s are caused by four families of virus: arenavirus (Lassa virus), filovirus (Ebola virus), bunyavirus (Rift Valley fever) and flavivirus (Dengue virus). Both anti-virals and vaccines have proven to be ineffective at treating VHF. Key characteristics of VHF are severe thrombocytopenia and endothelial cell dysfunction and these two are linked as one leads to the other. While the role of platelets in thrombosis and haemostasis is well established their role in the innate immune system is less well recognised. As the first responders to any injury platelets play an important role in orchestrating the immune response to pathogens. Once activated secreted anti-microbial peptides are bactericidal to many bacteria and secreted cytokines attract other immune cells to the site of injury. However, over-stimulation of platelets during infection plays a role in pathogenesis leading to disseminated intravascular coagulation. Exposure to a second serotype of Dengue virus leads to binding of non-neutralising antibody, which mediates an interaction with macrophage and platelet FcγRIIa. The interaction with macrophages allows viral internalisation and enhanced replication while the interaction with platelets leads to platelet activation and thrombocytopenia. As a result we selected FcgRIIa as a potential drug target in dengue haemorrhagic fever. A pharmacophore was generated from a molecular model of FcγRIIa binding to IgG and use to screen a virtual library of small molecules. The best hits were selected and mapped to an in-house scaffold. Over a hundred derivatives of this scaffold were then synthesised and screened for their ability to inhibit platelet adhesion to IgG as well as Staphylococcus aureus-induced platelet aggregation. Currently the best compound has an IC50 of 1 μM in these assays. In conclusion inhibition of platelet receptors for viruses is a potential treatment strategy for preventing VHF.

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