Technology

Our proprietary Tailored Covalency platform is central to what differentiates our drug candidates from conventional small molecules.

We believe that bonding matters. Our pioneering approach uses proprietary technology and know-how to create powerful bonds that allow us to tailor the effects we want. Our Tailored Covalency® platform has consistently and efficiently enabled us to make both reversible covalent and irreversible covalent small molecule inhibitors that bind very specifically to the desired known target in the body.

Principia’s Tailored Covalency is revolutionizing small molecule design and development. Historically, small molecule drug design has remained largely unchanged, relying on elevated and sustained blood levels of the drug to overcome a drug constantly going off and on the target. However, constant drug exposure can lead to unintended binding to off-targets and unwanted side effects. By optimizing residence time where drugs bind on their target and for how long, we hope to limit systemic exposure, potentially minimizing off-target effects while achieving high clinical benefit.

Our precision bonding enables our molecules to specifically attach to the desired target for a long period of time, without the need for constant, elevated drug levels.

The power of this unique approach is achieved by having two binding interactions: one with the desired target site and one with a unique adjacent covalent site. This “double lock and key” design results in a high-affinity, covalent bond with the desired target, thus providing both drug durability and reducing interactions with off-targets. Principia’s new approach is designed to optimize the risk benefits of small molecules by potentially improving treatments for patients.

The medicinal chemistry underlying Tailored Covalency enables us to select where and for how long binding takes place. Our goal is to optimize these bonds so that our drug candidates remain bound to the desired target in order to deliver desired clinical effect while minimizing off-target binding and long systemic exposure. Through our pioneering discovery platform, we can reproducibly develop oral small molecules that have the potential to be best-in-class and highly differentiated based on their mode of action, selectivity and target residence time.

By optimizing for target residence time, our drug candidates remain bound to the target but otherwise clear the body rapidly.

Double lock and key solution of Tailored Covalency results in potential enhanced selectivity and extended residence time.

Our proprietary “double lock-and-key” solution results in small molecules with tailored selectivity for the desired targets.

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. This “double lock-and-key” solution is central to our design of small molecules with high selectivity for their targets. 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 provides the opportunity to purpose-design our drug candidates more rapidly for specific indications as compared to conventional methods. We also believe we can reproducibly develop small molecules that have the potential to be best-in-class and highly differentiated based on their mode of action, selectivity and target residence time.

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