Bispidine-amino acid conjugates act as a novel scaffold for the design of antivirals that block Japanese encephalitis virus replication.
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.


RESULTS
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
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.
Department of Chemistry, Indian Institute of Technology, New Delhi, India. haridasv@chemistry.iitd.ac.in
V
V
Haridas
Kullampalayam Shanmugam
KS
Rajgokul
Sandhya
S
Sadanandan
Tanvi
T
Agrawal
Vats
V
Sharvani
M V S
MV
Gopalakrishna
M B
MB
Bijesh
Kanhaiya Lal
KL
Kumawat
Anirban
A
Basu
Guruprasad R
GR
Medigeshi
D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004664:Encephalitis Virus, Japanese / Q000187:drug effects* / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009474:Neurons / Q000821:virology; D018116:Vesiculovirus / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects / Q000502:physiology
D000596:Amino Acids; D000998:Antiviral Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495809:bispidine