Covalent Biologics
Constructive.bio installs electrophilic warhead ncAAs at genetically defined positions adjacent to target-binding interfaces, enabling irreversible covalent bond formation between biologic and target. This converts reversible binders into covalent drugs with prolonged pharmacological effect, reduced dosing frequency, and lower systemic exposure — capabilities impossible with conventional amino acids.
The Problem
Most biologics bind reversibly, requiring sustained high plasma concentrations to maintain target occupancy. This drives frequent dosing (weekly or biweekly injections), high per-dose costs, and off-target effects from systemic exposure. Small-molecule covalent drugs (e.g., BTK inhibitors) have demonstrated the pharmacological advantages of irreversible binding, but no established method exists to engineer covalent reactivity into proteins or peptides with positional precision.
Our Approach
Constructive.bio’s expanded genetic code incorporates ncAAs bearing electrophilic warheads — including fluorosulfate (SuFEx chemistry), acrylamide, and vinyl sulfonamide groups — at ribosomal level. These are placed at computationally identified positions proximal to nucleophilic residues (Cys, Lys, His, Tyr) on the target protein surface. Upon reversible binding, the proximity-driven reaction forms an irreversible covalent bond. Because the warhead is genetically encoded at a single defined position, the reactivity is site-specific and predictable.
Key Capabilities
Site-specific warhead placement at genetically defined positions via expanded genetic code
Multiple warhead chemistries: fluorosulfate (SuFEx), acrylamide, vinyl sulfonamide
Proximity-driven covalent bond formation — no off-target reactivity
Prolonged target engagement enabling reduced dosing frequency