Powered by Tailored Covalency®

Principia Biopharma challenges traditional drug discovery by utilizing its proprietary Tailored Covalency technology to discover new medicines that combine the dosing convenience of an oral small molecule drug with the specificity of an antibody.

Benefit of covalent inhibitors

Long effect – short exposure: Long lasting efficacy without the need to continuously expose the body to circulating drug

Additional benefits of making covalent inhibitors reversible

Power of covalency with the safety of reversibility: Superior therapeutic strength without the consequences of permanent modification of proteins

Specificity of an antibody with the convenience of a pill: Oral therapy with fewer off-target effects

Residence time by design: Tuning the duration of drug effect on the target

 

Tailored Covalency® Technology

A covalent bond is a strong, long-lasting interaction between a drug and its target. Principia’s proprietary technology enables the formation of a covalent bond between the drug and a specific cysteine amino acid in the therapeutic target without making that bond permanent (i.e., irreversible). Principia’s Tailored Covalency technology expands the benefits of conventional irreversible covalent approaches to include an innovative new reversible covalent bond alternative.

The synergy of the reversible covalent bond coupled with the “lock and key” drug protein interactions of classical small molecule drugs imparts profound efficacy and selectivity. When the “lock and key” interactions are disrupted during the natural protein turnover and recycling process, the cysteine bond breaks, and the drug is released from the protein. This intrinsic property avoids the potential for side effects resulting from permanently modified drug-bound proteins.
 

Principia’s Drug Discovery Process

Principia increases efficacy by focusing on the length of time the drug engages the target “residence time”, rather than drug exposure in the systemic circulation. This fundamentally different way of discovering and optimizing drugs is made possible by utilizing in-house knowledge of cysteine binding chemistries, methods to model specific binding interactions, and the experience of how to measure the rate at which the drug releases from the target in vitro and in vivo. Knowledge gained from this revolutionary approach allows Principia to systematically optimize residence time and uncouple pharmacodynamics from pharmacokinetics. This means the duration of target inhibition is no longer just a function of drug exposure, but a tunable feature that can be optimized early in the discovery process.

Principia can efficiently transform weakly binding compounds into drug candidates that have high potency and a high degree of selectivity. This rapid optimization of drug candidates results in an accelerated path to clinical development.

 

Matching the level of covalent inhibition to the requirements of the disease



 

Relevant cysteine containing targets are abundant across protein classes

Principia has developed a proprietary algorithm for quickly determining target suitability for its reversible covalent approach.