Computational Development of Novel Dyslipidemia Therapeutic Candidates to Disrupt ApoC-III Conformation

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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.