The nucleic acid polymers DNA and RNA contain the information for the amino acid sequences of proteins, and proteins are involved in the replication of the nucleic acid polymers. Terrestrial life uses nucleic acid polymers as the genetic molecules and, most often, proteins as the functional molecules. Therefore, our findings suggest that the prebiotically abundant amino acids were used for creating stable protein structures and other amino acids with functional side chains were recruited to achieve efficient catalysis. The inconsistent amino acids appeared to be important for catalytic activity but not for stability. Notably, many but not all of the reduced-set amino acids coincide with those plausibly abundant in primitive Earth. We eventually found that two convergent sequences, each comprised of a 13-amino acid alphabet, folded into soluble, stable and catalytically active structures, even though their stabilities and activities were not as high as those of the parent protein. Herein we comprehensively and systematically reduced the size of the amino acid set constituting an ancestral nucleoside kinase that was reconstructed in our previous study. Nevertheless, few experimental tests of this issue with arbitrarily chosen amino acid sets had been reported prior to this report. However, earlier protein synthesis was plausibly much simpler than modern one and utilized only a limited set of amino acids. Our findings will provide a novel platform to develop effective inhibitors of JEV and perhaps other RNA viruses causing encephalitis.Modern organisms commonly use the same set of 20 genetically coded amino acids for protein synthesis with very few exceptions.

We have demonstrated that the amino-acid conjugates of 3,7-diazabicyclononane can serve as a molecular scaffold for development of potent antivirals against encephalitic viruses. 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. Viral inhibition was at a stage post-entry and prior to viral protein translation possibly at viral RNA replication. We identified a tryptophan derivative, Bisp-W, which at 5 ВµM concentration inhibited JEV infection in neuroblastoma cells by more than 100-fold. We have synthesized derivatives of bispidine conjugated with amino acids and found that hydrophobic amino acid residues showed antiviral properties against JEV. In this study we have identified 3,7-diazabicyclononane, commonly called bispidine, as a privileged scaffold to synthesize effective antiviral agents. 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.

Protein secondary structure mimetics are excellent candidates for inhibiting the protein-protein interactions and therefore serve as an attractive tool in drug development. 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. Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in South and South-East Asia.

Protein scaffold 5 amino acids