Newly launched Enlaza aims to bring covalency to biologics

Enlaza Therapeutics has launched with $61 million in seed funding to extend to protein-based drugs the option of covalency, a functionality that is now present only in small-molecule medicines. The company, based in La Jolla, California, says it’s the first to enable covalent biologics, thanks to technology licensed from the lab of pharmaceutical chemist Lei Wang at the University of California, San Francisco.

As the name suggests, covalent drugs bind to their targets via long-lasting covalent bonds. Compared to noncovalent drugs that bind reversibly, covalent medicines have a longer action time and higher potency at smaller quantities. Given their permanent ties, the selectivity of covalent drugs is a priority, so they don’t hitch to the wrong targets.

Covalent drugs usually contain an electrophilic motif that reacts with a nucleophilic center on a human protein target. Most covalent small-molecule drugs bind to cysteine on their targets, though several research groups are also targeting lysine residues.

To bring covalency to biologics, Enlaza attaches an unnatural amino acid to the therapeutic protein as the covalent tethering point. This designer amino acid is engineered for low reactivity. A more reactive electrophile would bind indiscriminately, including to the wrong targets.

Selectivity comes from the rest of the protein drug, given that proteins fold into highly specific shapes to match their targets. The idea is that the engineered protein will home in on its target, bringing the unnatural amino acid close enough to overcome its reticence and create a covalent bond with the target’s nucleophile. Enlaza’s CEO, Sergio Duron, calls it “handcuffing the drug to the desired target.”

Enlaza is currently developing covalently binding antibody-drug conjugates and radiotherapeutic ligands for oncology. But the company emphasizes that its covalent biologics platform is versatile enough for other disease applications.

“Our technology installs a covalency onto any standard protein biologics,” Duron says. “This is an opportunity to improve safety and efficacy” of protein drugs.