Hemagglutinin
(HA) of influenza type A viruses is a target for the development of entry
inhibitors as potential anti-viral drugs. Derivatives of HA’s natural ligand,
neuraminic acid, are capable of interacting strongly with it.
We hereby
report the in silico design and
synthesis of a glycoside of derivatized neuraminic acid as a ligand for
hemagglutinin H5 of avian influenza. This ligand is a valuable tool for understanding
the H5 binding pocket and developing a QSAR model.
Molecular
modeling has been performed based on the crystal structure of
A/Duck/Singapore/3/97 (H5N1) HA published by Wiley et al.[1] (PDB: 1JSO). A variety of glycerol-sidechain
modifications and aglycones have been designed, synthesized and tested for
binding affinity via STD-NMR-spectroscopy[2] and SPR-spectrometry.
The most successful variations for each modification of the neuraminic acid
were then integrated in a second iteration of in silico design, yielding very promising ligands. These were secondary
amines of sidechain-truncated neuraminic acid with an aromatic aglycone bound
by a peptidic linker. The synthesis of this highly functionalized molecule has
been realized by a convergent strategy starting with N-acetylneuraminic acid amongst others. After characterization of
the binding affinity by STD-NMR-spectroscopy and SPR-spectrometry, the obtained
data will be used for evolving a QSAR model, which will be utilized for the de novo design of an artificial ligand.
References
[1] Y. Ha,
D. J. Stevens, J. J. Skehel, D. C. Wiley, Proc.
Natl. Acad. Sci., 2001, 98, 11181-11186.
[2] M.
Mayer, B. Meyer, Angew. Chem. Int. Ed.,
1999, 38, 1784-1788.
