STRUCTURE BASED DESIGN OF INHIBITORS FOR FLU NEURAMINIDASE

INFLUENZA IS A SERIOUS DISEASE THAT CAUSES ABOUT 10,000 TO 20,000 DEATHS IN AN AVERAGE SEASON. EVEN THOUGH VACCINES HAVE BEEN AVAILABLE FOR A NUMBER OF YEARS, THEY CONTROL INFLUENZA POORLY IN THE HUMAN POPULATION. THE VACCINE THERAPY'S LACK OF EFFECTIVENESS IS DUE TO THE VIRUS' CAPACITY TO CHANGE ITS ANTIGENIC STRUCTURE AND ESCAPE THE HOST'S IMMUNE SYSTEM. A MORE EFFICIENT WAY TO CURB INFLUENZA MAY BE VIA ANTI-VIRAL AGENTS WHICH INTERFERE WITH CRUCIAL VIRAL FUNCTIONS. ONE OBVIOUS TARGET IS THE ENZYME RESPONSIBLE FOR THE SPREAD OF THE VIRUS, NEURAMINIDASE. MORE THAN 50 YEARS OF EMPIRICAL RESEARCH HAVE NOT PRODUCED ANY EFFECTIVE ANTI-INFLUENZA AGENTS. THE ONLY DRUG CURRENTLY APPROVED IN THE U. S. FOR THE PROPHYLAXIS AND THERAPY OF INFLUENZA INFECTION IS AMANTADINE HYDROCHLORIDE. HOWEVER, MUTANTS RESISTANT TO AMANTADINE ARE READILY ISOLATED. THUS, THERE IS A CLEAR NEED FOR A MORE SUCCESSFUL APPROACH THAN THE EMPIRICAL METHODS HAVE BEEN. THE OBJECTIVE OF THIS PROJECT IS TO DETERMINE THE MOLECULAR ARCHITECTURE AND TO UNDERSTAND THE MECHANISM OF ACTION OF THE INFLUENZA A NEURAMINIDASE. THE LONG-TERM GOAL IS TO DESIGN AND SYNTHESIZE ACTIVE- SITE INHIBITORS OF NEURAMINIDASE WHICH ARE EFFECTIVE AND SAFE ANTI-VIRAL AGENTS AGAINST INFLUENZA IN THE HUMAN POPULATION.