Project Grant S10OD040101

OCTET-RH16 SYSTEM - PROJECT SUMMARY/ABSTRACT THE CENTER FOR STRUCTURAL BIOLOGY, LOCATED IN THE LIFE SCIENCES INSTITUTE, IS A COMPREHENSIVE STRUCTURAL BIOLOGY RESOURCE FOR RESEARCHERS AT UNIVERSITY OF MICHIGAN (U-M) WHOSE MISSION IS TO PROVIDE ACCESS TO STATE-OF-THE-ART FACILITIES AS WELL AS EXPERTISE AND TRAINING ON ALL ASPECTS OF PROTEIN PRODUCTION AND CHARACTERIZATION THROUGH STRUCTURE DETERMINATION AND ANALYSIS. WE ARE REQUESTING FUNDS TO PURCHASE AN OCTET-RH16 SYSTEM EMPLOYING BIO-LAYER INTERFEROMETRY (BLI) TECHNOLOGY TO CALCULATE THE RATE OF ASSOCIATION (KA), RATE OF DISSOCIATION (KD) AND AFFINITY CONSTANTS (KD) FOR BIOMOLECULAR INTERACTIONS IN REAL-TIME. TO RUN A SUCCESSFUL DRUG DEVELOPMENT PROGRAM, OF WHICH U-M IS A LEADER HAVING CONTRIBUTED TO THE MOST FDA APPROVED DRUGS OF ANY UNIVERSITY IN THE US (PATRIDGE ET AL., DRUG DISCOVERY TODAY 20, 1182-1187, 2015), ACCESS TO TECHNOLOGY THAT MEASURES THE KINETICS OF BIOMOLECULAR INTERACTIONS OF DRUG-LIKE MOLECULES AND BIOLOGICS TO THEIR TARGETS TO PROVE TARGET ENGAGEMENT AND RANK ORDER THE COMPOUNDS/BIOLOGICS IS ESSENTIAL TO THE OPTIMIZATION OF LEADS FOR CLINICAL TRIALS. THIS SYSTEM WILL REPLACE OUR CURRENT FAILING OCTET-RED SYSTEM, WHICH IS A HIGH-DEMAND INSTRUMENT AND WHOSE END OF SERVICE LIFE WAS JULY 2019. CURRENTLY THERE ARE NO OTHER BLI INSTRUMENTS ON CAMPUS AVAILABLE TO OUR CENTER USERS. OUR CURRENT USERS ARE DEVELOPING THERAPEUTICS TO TREAT OR PREVENT A BROAD RANGE OF DISEASES. THEY ARE DEVELOPING NEW VACCINES, NEW ANTIBIOTICS, NEW THERAPIES TO COMBAT NEURODEVELOPMENTAL DISORDERS SUCH AS AUTISM, NEW THERAPEUTICS AGAINST BLOOD CANCERS SUCH AS MYELOPROLIFERATIVE NEOPLASM AND ACUTE MYELOID LEUKEMIA, NEW THERAPEUTICS AGAINST CASTRATION-RESISTANT PROSTATE CANCER, AND SYSTEMIC AND OCULAR TOXOPLASMOSIS IN VULNERABLE POPULATIONS. THEY ARE ALSO ENGINEERING BIOSYNTHETIC PATHWAYS TO DEVELOP NEW DRUGS OR IMPROVE EXISTING ONES. THE NEW OCTET-RH16 WILL DOUBLE THE NUMBER OF SAMPLES THAT WE CAN MEASURE IN PARALLEL (16) AND INCREASE THE NUMBER OF SAMPLES WE CAN MEASURE IN A SINGLE EXPERIMENT BY 8-FOLD, THUS INCREASING OUR THROUGHPUT BY 700%. IN ADDITION, THE REQUIRED SAMPLE VOLUMES WILL DECREASE BY 5-FOLD. THE NEW REGENERATION AND RE-RACKING STANDARD FEATURE WILL BE COST SAVING AS IT ALLOWS THE REUSE OF BIOSENSORS. THIS INCREASE IN PRODUCTIVITY AND RELIABILITY ALONG WITH THE DECREASE IN OPERATING COST WILL OPEN NEW AVENUES OF RESEARCH FOR THE U-M RESEARCH COMMUNITY. IT WILL PROVIDE AN OPPORTUNITY TO DIRECTLY SCREEN TARGETS AGAINST SMALL DRUG-LIKE CHEMICAL LIBRARIES HOUSED AT THE U-M CENTER FOR CHEMICAL GENOMICS, FOR EXAMPLE THE PRESTWICK LIBRARY, WHERE 95% OF THE COMPOUNDS ARE DRUGS APPROVED BY THE FDA-, EMA-, OR OTHER AGENCIES.