Our Approach and Platform

We are challenging the premise of oral drug design by using our proprietary Tailored Covalency platform to create therapies that are optimized for residence time, the duration of time that a drug binds to its target. We believe that our platform enables us to purpose-design and develop small molecule inhibitors of enzymes and receptor ligands with potencies and selectivities that rival those of injectable biologics, yet maintain the convenience of a pill.

Standard small molecule drugs have a short residence time and, therefore, require dosing regimens that sustain minimum concentration levels in the blood at all times to maintain beneficial effects on the target. By optimizing for target residence time, our drug candidates remain bound to the target but otherwise clear the body rapidly, as exemplified in the movie below. We believe this minimizes both off-target effects and total exposure of the drug while achieving high clinical benefit.


Double lock and key solution of Tailored Covalency results in superior selectivity and extended residence time

Guided by molecular modeling, we design small molecule drug candidates with two components, or keys, that fit the non-covalent features (the first lock) and the covalent elements (the second lock) of the target in the binding pocket. We believe that this “double lock-and-key” solution results in small molecules with high selectivity for their targets, thus reducing off-target activity. In contrast, the single-key solution typical of many standard small molecule drugs may allow the molecule to bind to multiple targets, which can lead to poor selectivity and result in unintended side effects. We believe our double lock-and-key solution has contributed to our ability to purpose-design multiple drug candidates for specific indications. The following diagram depicts our double lock-and-key solution:

Tailored Covalency graphic

Our suite of covalent technologies that we incorporate into our drug designs falls into two general categories that can be used to optimize residence time:

Reversible covalent compounds have a unique feature where the covalent bond between the inhibitor molecule and the target protein is fully reversible and, thus, does not permanently modify the target protein. Because the covalent bond is fully reversible, off-target binding is transient and of limited consequence. Another benefit of the reversible covalent solution is that the residence time of the molecule can be tailored. As a result, we can design molecules with varying residence times, evaluate their efficacies and then select drug candidates based on optimized properties.

Irreversible covalent compounds are designed to provide maximal occupancy to drive efficacy by permanently inhibiting the target protein. Because the covalent bond between the molecule and the target protein is irreversible, the target protein is permanently modified and, thus, the duration of the inhibition is determined by the length of time that it takes for the body to produce new replacement target proteins. When incorporating this covalent approach, we design drug candidates that require a low daily dosage in order to limit the amount of the drug that circulates in the body and, thus, reduce the likelihood of off-target effects.

Principia’s Drug Discovery Process

This new approach to small molecule drug discovery is both highly efficient by industry standards and reproducible, as we have produced three new drug candidates, resulting in four clinical programs in our first seven years of operations.

We believe this process is highly reproducible with a rapid cycle time, as shown in the graphic below.