**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME (PRRS), CAUSED BY PRRS VIRUS (PRRSV), IS THE MOST ECONOMICALLY DEVASTATING DISEASE AFFECTING SWINE INDUSTRY WORLDWIDE. THE SOWS WITH PRRS EXHIBIT REPRODUCTIVE PROBLEMS SUCH AS ABORTION, PREMATURE BIRTH, AND STILLBIRTH. ALL PRRSV INFECTED PIGS DEVELOP SYMPTOMS SUCH AS COUGHING, DIFFICULTY BREATHING, INAPPETENCE, POOR WEIGHT GAIN, WITH DISTRESS COMPLICATED BY SECONDARY INFECTIONS PROVOKING MORE SERIOUS DISEASES AND MORTALITY. BECAUSE OF THE HIGH GENETIC HETEROGENEITIES OF PRRSV, CURRENTLYNO BROADLY EFFECTIVE VACCINE IS AVAILABLEAGAINST PRRS. BASED ON OUR RECENT STUDIES, WE PLAN 1) TO EVALUATE THE INHIBITORY EFFECT ON PRRSV INFECTION IN PIGS BY A NATURAL COMPOUND (AND ITS HERB FORM) THAT CAN DOWNREGULATE THE PRRSV SPECIFIC RECEPTOR EXPRESSION IN PIG CELLS TO INHIBIT PRRSV-INFECTION, AND TO EVALUATE THE DERIVATIVES AND ANALOGUES OF THIS COMPOUND TO INHIBIT PRRSV-INFECTIONIN VITRO; 2) TO DEVELOP A LEAD COMPOUND FROM THE DERIVATIVES/ANALOGUES OFANOTHER SMALL MOLECULETHAT BLOCKS THE INTERACTION OF PRRSV WITH ITS RECEPTOR AND THEREFORE PRRSV INFECTION, AND EVALUATE THEIN VIVOTOXICITY AND EFFICACY OF THIS LEAD COMPOUND ON INHIBITING PRRSV INFECTION IN PIGS; AND 3) TO PERFORM HIGH-THROUGHPUT SCREENING TO IDENTIFY ADDITIONAL COMPOUNDS THAT BLOCK PRRSV BINDING TO ITS RECEPTOR AND THEREFORE THE VIRAL INFECTION. THE DATA GENERATED FROM THIS PROJECT WILL IDENTIFY NOVEL VETERINARY MEDICATIONS TO BLOCK PRRSV INFECTION IN PIGS. THIS STUDY WILL ALSO GENERATENEW KNOWLEDGE ON THE PRRSV SPECIFIC RECEPTOR EXPRESSION AND ITS INTERACTION WITH PRRSV,TO FACILITATE THE IDENTIFICATION AND TEST OF NEW THERAPEUTICS TO CURTAIL THE PRRS PANZOOTIC.