Themagglutinin (HA) and neuraminidase (NA; sialidase) are responsible for immunogenicity and infection process of Influenza virus. The successful molecular design of inhibitors against NA based on X-ray crystallography shows a direction of our future development of pharmaceutical drugs.
Most of the commercial Influenza drugs are targeted toward NA. A reason for this is because it is easy. NA has deep cavity inside it there are catalytic site, in such case we can expect various binding enhancements. The situation differs in HA binding site against silalyated glycan structures. The biding site is shallow and there is no ionic side chains of constituting amino acids available for designing anti-HA agents.
Regardless of the difficulty in anti-HA drugs. We proposed a possibility of inhibiting both NA and HA with a hope that such a compound may prevent emergence of drug resistant virus strains. Let us consider a provability of emergence of resistant strain is 1/100,000. The number now is applied to two different RNA coding HA and NA. This makes a chance for the virus to escape from the dual functional drug extremely low.
For this reason, we examined our hypothesis by synthesizing a series of sialic acid derivatives. One of the important idea for the designing molecules is to find a spot in the sialic acid residue that is not recognized by both HA and NA.
Reference
Sun, X.-L. et al. Eur. J. Org. Chem., 2000, 14, 2643-2653.
Guo, C.-T. et al. Glycobiology, 2002, 12, 183-190.
インフルエンザウイルスの表面にある２種類のタンパク質を同時に阻害しようとする「デュアルファンクション」の考え方は、単に面白い以上の効果を期待することができます。仮に１／１０００００の確立で薬剤耐性株が出現したとすると２つ阻害すると、うまく行けばこの２乗の確率となるので、耐性株の出現を押さえ込むことができると考えられます。
