Project Grant R43HL170808

COMPUTATIONAL DEVELOPMENT OF NOVEL DYSLIPIDEMIA THERAPEUTIC CANDIDATES TO DISRUPT APOC-III CONFORMATION - PROJECT ABSTRACT CARDIOVASCULAR DISEASE (CVD) IS A SIGNIFICANT THREAT IN THE UNITED STATES AND DEVELOPING COUNTRIES ACROSS THE GLOBE. WIDELY ASSOCIATED WITH ELEVATED LOW DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C), THERAPEUTIC INTERVENTIONS ARE PRIMARILY FOCUSED ON REDUCTION OF LDL-C PLASMA LEVELS. DESPITE THE ABILITY TO THERAPEUTICALLY REACH THESE TARGET LEVELS, MANY PATIENTS MAINTAIN HIGH CARDIOVASCULAR RISK PROFILES. A CAUSAL CONTRIBUTOR TO THIS THERAPEUTIC PARADOX IS THE DEVELOPMENT OF TRIGLYCERIDE-RICH LIPOPROTEIN (TRL) PARTICLES, HIGHLY ATHEROGENIC REMNANT PARTICLES THAT ARE THE RESULT OF IMPAIRED LIPASE CATABOLISM. EXHIBITING RESISTANCE TO CURRENT FDA APPROVED LDL-C LOWERING MEDICATIONS, THESE PARTICLES MAINTAIN SIGNIFICANT CARDIOVASCULAR RISK DESPITE THE OVER LOWERING OF LDL-C. IT HAS BEEN DETERMINED THAT HIGH APOLIPOPROTEIN C-III (APOC-III) IS A HALLMARK OF TRL PARTICLES. THE SINISTER NATURE OF APOC-III IS WELL ESTABLISHED AS IT POSSESSES KEY FUNCTIONS THAT INCLUDE, BUT ARE NOT LIMITED TO; INHIBITION OF LIPOPROTEIN LIPASE (LPL), IMPAIRMENT OF HDL CHOLESTEROL EFFLUX AND RETARDATION OF LIPOPROTEIN PARTICLE HEPATIC UPTAKE. AS A POTENTIAL SOLUTION, IMBP IS DEVELOPING NEW THERAPEUTIC COMPOUNDS THAT TARGET APOC-III. OUR CURRENT RESEARCH EFFORTS HAVE COMPUTATIONALLY IDENTIFIED THE POTENTIAL TO INDUCE A CONFORMATIONAL DISTORTION IN THE APOC-III TARGET UPON BINDING. DUE TO A HIGHLY FLEXIBLE HINGE REGION IN THE MOLECULE THAT IS NECESSARY FOR APOC-III TO STABILIZE ON LIPOPROTEIN PARTICLES, THE INDUCTION OF A CONFORMATIONAL CHANGE COULD PROVIDE A UNIQUE THERAPEUTIC MODE OF ACTION IN ACTION FOR REDUCING TRL LEVELS. THIS PROOF-OF-CONCEPT WORK IS TO COMPUTATIONALLY REENGINEER A CURRENT PROPRIETARY THERAPEUTIC CANDIDATE TO AUGMENTED APOC-III DISTORTION CAPABILITIES. AN EXPRESSION LIBRARY WILL THEN BE EXPRESSED AND TOP CANDIDATES WILL BE FUNCTIONALLY TESTED FOR BINDING. SPLIT INTO 2 SPECIFIC AIMS, THE FINAL EVALUATION OF FEASIBILITY TESTING WILL DETERMINE THE DEGREE OF DISTORTION THAT IS ACHIEVED AS A CONSEQUENCE OF BINDING. THE MILESTONE FOR THIS FINAL AIM IS THE IDENTIFICATION OF A MOLECULE THAT BINDS APOC-III AND CREATES A MEASURABLE CHANGE IN ITS CONFORMATION EXHIBITED AS AN INCREASE IN THE PROTEIN'S END TO END DISTANCE. THE SATISFACTION OF THIS MILESTONE WOULD LEAD TO A SBIR PHASE 2 PLAN THAT WOULD FURTHER EVALUATE THE INFLUENCE THAT AN ARTIFICIALLY INDUCED APOC-III CONFORMATIONAL DISTORTION COULD PLAY IN DESTABILIZING ITS LIPOPROTEIN PARTICLE BINDING CHARACTERISTICS AND ASSIST IN PLASMA CLEARANCE THAT WOULD CULMINATE IN PRE-CLINICAL TESTING.