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Structure-Based Design of Inhibitiors Targeting Filovirus Endosmal Receptor Binding Site to Block Viral Entry
Filoviruses can cause deadly outbreaks in humans with high mortality rates up to 90% so that they pose a great threat to the public health. Filoviruses are enveloped single-stranded negative-sense RNA viruses. The envelope glycoprotein (GP) is the only viral protein on the virion surface which is critical for virus infection. It is known that the filovirus infection is mediated by the cellular endosomal receptor Niemann-Pick C1 (NPC1). Thus, it is certain that blocking the NPC1 receptor binding will prevent the infection.This research has focused on the structure-based design targeting the NPC1 receptor-binding site (RBS) to block the receptor binding. Three major structural approaches are applied for the deigning. Firstly, by using an In silico screening approach to perform virtual compound screening against the RBS, twenty-six top-hit compounds had evaluated by in vitro cell-based assays against pseudotyped or replication-competent filoviruses. Two classes (A and U) (Appendix C) of compounds are identified to have potent inhibitory activities against both Ebola and Marburg viruses. The IC50 (50% inhibitory concentration) values are in the lower level of micromolar concentrations. Secondly, using available binding structural information from the co-crystal structures of the viral GP with the receptor NPC1 or with monoclonal antibodies, we conducted ligand-based design of peptide inhibitors to target the RBS. The designed peptides were tested for their activities in vitro. The results indicated that these peptides exhibited strong activities against both Ebola and Marburg virus infection.Finally, from another similar structural binding of HIV receptor CD4 and GP120, we tested CD4 and CD4-mimetics and surprisingly found that the human CD4 and CD4-mimetic compounds have the activities against filovirus infection. All these inhibitors identified indicated that the RBS is an idea target for drug design and development.
Wang, Liu Leah, "Structure-Based Design of Inhibitiors Targeting Filovirus Endosmal Receptor Binding Site to Block Viral Entry" (2022). ETD collection for University of Nebraska-Lincoln. AAI30000122.