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

> **NIH NIH R43** · IMETABOLIC BIOPHARMA CORPORATION · 2023 · $283,123

## Abstract

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.

## Key facts

- **NIH application ID:** 10760187
- **Project number:** 1R43HL170808-01
- **Recipient organization:** IMETABOLIC BIOPHARMA CORPORATION
- **Principal Investigator:** Urban A Kiernan
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $283,123
- **Award type:** 1
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10760187

## Citation

> US National Institutes of Health, RePORTER application 10760187, Computational Development of Novel Dyslipidemia Therapeutic Candidates to Disrupt ApoC-III Conformation (1R43HL170808-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10760187. Licensed CC0.

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