THEVARROAMITE (VARROA DESTRUCTORANDERSON AND TRUEMAN), AN OBLIGATORY ECTOPARASITE OF THE HONEY BEE, IS A MAJOR THREAT TO THE MAINTENANCE OF HEALTHY BEE COLONIES. THE USE OF CHEMICAL ACARICIDES IN BEEHIVES TO CONTROLVARROAMITES REQUIRES STRINGENT CRITERIA OF NONTOXICITY TO HONEY BEES AND VERTEBRATES. WE PROPOSE A BIORATIONAL APPROACH FOR THE DEVELOPMENT OF BEE-SAFE ACARICIDES THAT TARGETS THEVARROAMITE-SPECIFIC NEUROPEPTIDERGIC SYSTEM REGULATED BY PROCTOLIN, A HIGHLY CONSERVED ARTHROPOD-SPECIFIC SMALL NEUROPEPTIDE RYLPT (ARG-TYR-LEU-PRO-THR). IN COMPARATIVE GENOMICS, WE FOUND THAT LEPIDOPTERA AND HYMENOPTERA LACK BOTH PROCTOLIN AND ITS RECEPTOR, OFFERING A HIGHLY SELECTIVE TOXICOLOGICAL TARGET IN THEVARRIAMITE. OUR PRELIMINARY STUDIES HAVE SHOWN THAT PROCTOLIN PEPTIDOMIMETICS, PEPTIDES CONTAINING UNNATURAL AMINO ACIDS FOR IMPROVING THE STABILITY AND BIOAVAILABILITY, HAVE LETHAL TOXIC ACTIVITIES ON THEVARROAMITE, WHILE IT SHOWED NO INDICATION OF TOXICITY TO THE HONEY BEE. FOUR OBJECTIVES OF THE STUDY ARE AS FOLLOWS; 1) HIGH THROUGHPUT SCREENING OF CHEMICAL LIBRARY, 2) STUDY OF BIOACTIVITY AND BIOAVAILABILITY OF PROCTOLIN PEPTIDOMIMETICS, 3) STRUCTURAL MODELING OF THE LIGAND DOCKING, AND 4) LABORATORY AND FIELD EFFICACIES OF THE TOXIC COMPOUNDS. THIS PROPOSAL AIMS TO EXPLORE THE SHORTEST PATH TO REACH TO THE DEVELOPMENT OF BEE-SAFE ACARICIDAL COMPOUNDS WHILE IT WILL ALSO BROADEN THE FUNDAMENTAL KNOWLEDGE IN THE BIOCHEMISTRY OF THE PROCTOLIN RECEPTOR AND LIGAND INTERACTION FOR PREPARING THE FUTURE TECHNOLOGY. THE IMMINENT PROBLEM OF THE CONSERVATION OF POLLINATORS AND APICULTURE IS ADDRESSED IN THIS PROPOSAL.