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Abstract
Using small angle X-ray scattering (SAXS) data, we reconstructed the scattering shape of the Hemagglutinin (HA) trimer protein from five different influenza strains. Comparison with the known crystal structures-based information aided in identifying volumes pertaining to the glycosylation in the HA trimers. By merging sequence information on HA proteins from pathogenic strains of influenza, we identified a novel druggable pocket composed of residues which remained conserved during evolution, lack propensity to be glycosylated, and play important role in maintaining interchain contacts in the pH-sensitive head group. To test our hypothesis that molecules reactive to this site may retard pH-induced opening of HA trimer in strain-independent manner, we performed in vitro screening of peptides representing interacting epitopes for their ability to retard pH-induced opening of HA trimers. Results brought forth that some of the 20 peptides tested can retard low pH-induced opening/association of HA proteins across different subtypes, thus propagating notion that the drug site and peptides identified here may pave way towards strain-independent anti-influenza molecules.
Acknowledgments
The authors acknowledge financial support from CSIR (SIP-10, FAC-03 and UNSEEN 12th five-year plan network project). KP and YSR are grateful to CSIR and UGC-CSIR for research fellowships. Travel to the synchrotron was supported by CSIR-India. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. This is IMTech communication number 011/2009.