2005 Fiscal Year Final Research Report Summary
Basic study of drug development for anti-influenza virus based on structural analysis of sialidase
| Project/Area Number |
16570104
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Structural biochemistry
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| Research Institution | High Energy Accelerator Research Organization (KEK) |
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Principal Investigator |
KATO Ryuichi High Energy Accelerator Research Organization (KEK), Institute of Materials Structure Science, Associate Professor, 物質構造科学研究所, 助教授 (50240833)
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| Co-Investigator(Kenkyū-buntansha) |
WAKATSUKI Soichi High Energy Accelerator Research Organization (KEK), Institute of Materials Structure Science, Professor, 物質構造科学研究所, 教授 (00332114)
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| Project Period (FY) |
2004 – 2005
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| Keywords | sialidase / neuraminidase / Neu2 / X-ray crystallography / three-dimensional structure / inhibitor / model building / complex |
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| Research Abstract |
Neuraminidases, or sialidases, are glycohydrolytic enzymes broadly present among species. They are found in viruses, bacteria and mammals, where they catalyze the removal of sialic acid on the non-reducing termini of complex carbohydrates, and act in infection processes, signal transduction, intercellular interactions, glycoconjugate degradation etc. The infectivity of some viruses such as influenza virus has been illustrated to be biologically dependent on sialidase's function. For instance, the influenza virus neuraminidase (NA) hydrolyzes the sialic acid from a receptor protein located at the surface of the host cell and recognized by newly generated virus particles. In such a way, NA helps for the propagation of newly formed virions. Therefore, the inactivation of NA results in stopping the propagation of the virus. From this point of view, NA is the target of drug designs for clinical treatment of the infection. Within species, sialidases diverge in their amino acid sequences, but assume a similar folding by means of a six bladed beta-propeller, and share almost identical active site architecture. Consequently, drugs targeted to one virus strain's NA expectedly acts on other strains as well. We solved the X-ray crystal structure of the human sialidase Neu2, both alone and in complex with a sialidase inhibitor 2-deoxy-2,3-dehydro-N-acetyl neuraminic acid (DANA). Furthermore, we also determined the complex structures of human sialidase Neu2 with some NA inhibitors such as Zanamivir or Peramivir. Comparing the structures with that of influenza virus NA, more specific drug developments without side effect could be discussed.
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