Our Science

Underdog’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.

Underdog’s Novel Approach:

Curing Atherosclerosis

Atherosclerosis is the world’s leading cause of death.

All-cause mortality risk-adjusted to account for atherosclerosis as the underlying cause of death.

Data from WHO and US Dept of HHS, 2017.

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.

Underdog 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

Underdog has now created proprietary, custom-engineered, nontoxic cyclodextrins designed to achieve high affinity and high specificity for the 7KC target.