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Background Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in South and South-East Asia. Lack of antivirals and non-availability of affordable vaccines in these endemic areas are a major setback in combating JEV and other closely related viruses such as West Nile virus and dengue virus. Protein secondary structure mimetics are excellent candidates for inhibiting the protein-protein interactions and therefore serve as an attractive tool in drug development. We synthesized derivatives containing the backbone of naturally occurring lupin alkaloid, sparteine, which act as protein secondary structure mimetics and show that these compounds exhibit antiviral properties. Methodology/Principal Findings In this study we have identified 3,7-diazabicyclo[3.3.1]nonane, commonly called bispidine, as a privileged scaffold to synthesize effective antiviral agents. We have synthesized derivatives of bispidine conjugated with amino acids and found that hydrophobic amino acid residues showed antiviral properties against JEV. We identified a tryptophan derivative, Bisp-W, which at 5 µM concentration inhibited JEV infection in neuroblastoma cells by more than 100-fold. Viral inhibition was at a stage post-entry and prior to viral protein translation possibly at viral RNA replication. We show that similar concentration of Bisp-W was capable of inhibiting viral infection of two other encephalitic viruses namely, West Nile virus and Chandipura virus. Conclusions/Significance We have demonstrated that the amino-acid conjugates of 3,7-diazabicyclo[3.3.1]nonane can serve as a molecular scaffold for development of potent antivirals against encephalitic viruses. Our findings will provide a novel platform to develop effective inhibitors of JEV and perhaps other RNA viruses causing encephalitis., Author Summary Japanese encephalitis virus is a mosquito-borne virus, which causes encephalitis primarily in children and is a major cause of encephalitis-related deaths in South and South-East Asian countries. Although new and safe vaccines are available for use, it is neither affordable nor readily available in endemic regions. Currently there are no antivirals for JEV treatment and developing new drugs against JEV is the need of the hour. In this study we used the backbone of the naturally occurring lupin alkaloid, sparteine to synthesize derivatives containing amino acid residues. We found that the conjugate consisting of the hydrophobic amino acid tryptophan, Bisp-W, inhibited virus replication in cell culture studies. We show that Bisp-W inhibits virus infection at a stage post-entry and at the level of viral RNA replication suggesting that this compound could serve as a potential therapeutic option for treating JEV infection. We believe that the chemical scaffold identified in this study could serve as a platform for synthesizing more potent antivirals that could be used to treat viral encephalitis.

We designed and synthesized bispidine-anchored peptides and showed that these peptides as small as B3 (containing four chiral α-amino acid residues) adopt a right handed helical conformation. Bispidine anchored linear peptide B3 adopts a helical conformation in solution and in the solid state.