Development of new influenza virus treatments based an the findings of triggering proteases for influenza virus entry into the cells and on the findings of protease-activating receptors

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Influenza virus infection including pandemic avian influenza virus in 2003 is one of the mast common infectious pathogens in humans and causes considerable morbidity and mortality. Recently inhibitors of influenza virus neuraminidase have been developed as anti-influenza drugs, which inhibit virus release from the cells at the budding stage. On the other hand, we have developed the inhibitar of virus envelope protein processing protease, which inhibit virus entry into the cells. In the term of this research project, we found four different bast cellular influenza virus envelope glycoprotein processing proteases, such as mini-plasmin, ectopic anionic trypsin, TMPRSS7 and TC30, other than tryptase Clara. These proteases distributed different locations in the airway and revealed different susceptibility for the virus envelope glycoprotein of various subtypes. Among them, expression of ectopic anionic trypsin increased in the lungs alter virus infection and may play a role in progression of virus spread and pneumonia. Mini-plasmin levels also increased at the inflammatory loci in the lungs after virus infection and accumulated on the cerebral capillaries through blood f low in mice having an impaired mitochondrial β-oxidation. In addition, accumulated mini-plasnmin destructed blood-brain barrier, resulting in brain edema and multiplication of the influenza virus in the brain capillaries. These findings implicate that disorder of mitochondrial β-oxidation and accumulation of mini-plasmin in the brain capillaries are the principal pathogens of influenza associated encephalopathy and Rye s syndrome. Based on these results, inhibitors of these virus envelope glycoprotein processing proteases may be important candidates for novel anti-influenza drugs. we are trying to find inhibitors of these processing proteases as anti-influenza drugs