All-cause mortality risk-adjusted to account for atherosclerosis as the underlying cause of death.
Data from WHO and US Dept of HHS, 2017.
OUR SCIENCE
Cyclarity's research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical excipient uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function.
Cyclarity’s Novel Approach:
- A true disease-modifying drug, and
- An efficient regimen to measure clinical modification of the disease
Curing Atherosclerosis
Atherosclerosis is the world’s leading cause of death.
The Mechanism of Atherogenesis
- Monocytes adhere to arterial wall
- Monocytes differentiate into macrophages
- Macrophages become foam cells (due to 7KC accumulation)
- 7KC-laden foam cells trigger:
- further inflammation
- damage to arterial infrastructure, and
- accumulation of more oxidized cholesterol
Proposed Mechanism of Action
Traditional drugs & animal models typically apply interventions far “upstream” (e.g., reduce the number of harmless circulating LDL particles, most of which will never be oxidized and contribute to atherosclerosis).
Hydroxypropyl Beta Cyclodextrin (HPβCD )
Cyclodextrins have countless industrial and pharmaceutical applications. Hydroxypropyl Beta Cyclodextrin is currently in clinical trials.
Cyclarity cyclodextrin derivatives have been designed to target only 7-ketocholesterol, the damaged cholesterol that actually drives atherosclerotic disease.
- Delivery of drug candidate
- Cyclodextrin enters arterial plaques
- Foam cells rehabilitated into healthy, functional macrophages
- 7KC is extracted and excreted
Our Process
Our iterative process combines bench chemistry and computational modeling to design, test, and evaluate the potential efficacy of engineered cyclodextrins as candidate active pharmaceutical ingredients. We use molecular dynamics simulations to provide clear visuals demonstrating how various cyclodextrins form complexes with 7KC.
Native beta cyclodextrin complexes well with 7KC, but it is relatively toxic to cells.
Hydroxypropyl beta cyclodextrin is extremely inert, but it needs a higher affinity for 7KC to be effective.
These simulations are then put to the test in the lab setting.
Efficacy of Engineered Cyclodextrins
- Normal cyclodextrins measured against binding to cholesterol
- Normal cyclodextrins measured against binding to 7KC
- Cyclarity-engineered cyclodextrins binding to 7KC (approx. 10x potency vs normal CDs)
Cyclarity has now created proprietary, custom-engineered, nontoxic cyclodextrins designed to achieve high affinity and high specificity for the 7KC target.
