Project Grant 20213941035936

HONEY BEE COLONIES ARE STRUGGLING TO SURVIVE. DURING THE 2019-2020 WINTER, INFECTION BY MITES, VIRUS, BACTERIA, AND FUNGI, AND REDUCED FORAGE AND PESTICIDES, CAUSED 44% COLONY MORTALITY (WWW.BEEINFORMED.ORG). THIS LEVEL IS A DRAMATIC INCREASE OVER THE 15%MORTALITY SEEN DURING THE LAST DECADES OF THE 20TH CENTURY. THE CONSEQUENCES OF SUSTAINED 40% COLONY LOSS AND REPLACEMENT ARE SERIOUS. ACCORDING TO BRET ADEE, THE NATION'S, AND WORLD'S LARGEST BEEKEEPER WITH 92,000 HIVES (NYT, FEB. 16, 2017), THE DIRECT IMPACT OF COLONY LOSS ON THE $691M APICULTURE INDUSTRY AND 11,774 COMMERCIAL BEEKEEPERS (IBISWORLD MARKET REPORT, DECEMBER 2020) IS $240M PER YEAR.DEFORMED WING VIRUS IS A MAJOR CAUSE OF HONEY BEE COLONY LOSS. TOGETHER WITH THE VARROA MITE, NEARLY EVERY DOMESTIC COLONY IS INFECTED (BEEINFORMED.ORG). THE VIRUS DISRUPTS NORMAL BROOD DEVELOPMENT, WEAKENS EMERGING BEES, AND KILLS ADULT BEES. DEFORMED WING VIRUS IS CONCENTRATED AND TRANSMITTED BY THE VARROA MITE, MAKING INFECTION AND INFESTATION A FEEDBACK LOOP THAT CAN OVERWHELM EVEN THE STRONGEST OF COLONIES.THERE IS NO FDA APPROVED TREATMENT FOR DEFORMED WING VIRUS, NOR ANY OTHER HONEY BEE VIRUS. THE GOAL OF THIS PROJECT IS TO DEVELOP AN EVIDENCE-BASED CURE.THE CHALLENGE TODAY IN SMALL MOLECULE DRUG DEVELOPMENT IS IDENTIFYING A DRUG CANDIDATE THAT IS BOTH SAFE AND EFFECTIVE. TYPICALLY, A CHEMISTRY TEAM TESTS HUNDREDS OF THOUSANDS OF COMPOUNDS. THE TEAM MUST STRIKE A BALANCE BETWEEN POTENCY, SIDE EFFECTS, ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION, AND TOXICITY. MOST FREQUENTLY, OPTIMIZATION FAILS NOT BECAUSE OF POTENTIAL BUT BECAUSE OF TIME AND MONEY.TO ADDRESS THIS BOTTLENECK, ATOMWISE (SAN FRANCISCO, CA) HAS DEVELOPED ITS ATOMNET PLATFORM (WWW.ATOMWISE.COM). THE TECHNOLOGY USES A STATISTICAL APPROACH THAT EXTRACTS THE INSIGHTS FROM MILLIONS OF EXPERIMENTAL AFFINITY MEASUREMENTS AND THOUSANDS OF PROTEIN STRUCTURES TO PREDICT THE BINDING OF SMALL MOLECULES TO PROTEINS. USE OF THIS APPROACH HAS RESULTED IN THE IDENTIFICATION AND SYNTHESIS OF 90 CHEMICALS THAT ARE PREDICTED TO BIND TO, AND DISRUPT, THE FUNCTION OF THE DEFORMED WING VIRUS 3C PROTEASE ENZYME. PROPER FUNCTIONING OF THIS ENZYME IS ESSENTIAL FOR VIRUS REPLICATION.THE GOAL OF THIS PROJECT IS TO ACHIEVE THE MOST CRITICAL MILESTONE OF A TREATMENT DEVELOPMENT PROGRAM, WHICH IS TO IDENTIFY A LEAD CHEMICAL THAT CAN BE DEVELOPED INTO A CURE FOR DEFORMED WING VIRUS DISEASE. THE TEAM HAS IN HAND 90 CHEMICALS OF DIVERSE STRUCTURE READY FOR PHYSICAL SCREEN AND THAT ARE PREDICTED TO BIND TO THE ACTIVE SITE OF THE ESSENTIAL DEFORMED WING VIRUS 3C PROTEASE ENZYME.THE TECHNICAL OBJECTIVES ARE TO PHYSICALLY SCREEN 90 CHEMICALS IN LIVE HONEY BEES AND BIOCHEMICAL ASSAY TO IDENTIFY A LEAD COMPOUND; TO ITERATEATOMNET AND PHYSICAL SCREEN, IF NECESSARY TO IDENTIFY A LEAD COMPOUND; TO DEVELOP THE CHEMICAL LEAD INTO AND INVESTIGATIONAL NEW ANIMAL DRUG; AND TO DETERMINE THE NEXT DEVELOPMENT STEPS AND SEEK FUNDING TO ACCOMPLISH THESE STEPS.