Medicinal chemists consistently face the battle of optimizing pharmacokinetic properties through chemical manipulation of a therapeutic molecule. In response to this challenge, we have developed a novel technology, which extends the exposure of a broad range of molecules. Utilizing nature and current clinical compounds as inspiration, the team was able to identify potent albumin binders through limited screening efforts. An X-ray structure allowed us to further understand the increased affinity and hypothesize grounds for the superiority of this binder. The lead albumin binder was optimized <i>in vivo</i> where we showed that this technology could tune the duration of exposure and pharmacodynamic response of a therapeutic molecule, depending on the albumin ligand conjugated. Within the technology application several new protein conjugation methods have also been discovered and applied including a histidine directed N-terminal selective modification and transglutaminase enzyme-mediated lysine functionalization. The albumin-based half-life extension technology was conjugated to several therapeutic molecules, dependably demonstrating extended exposure. Here the discovery, optimization, and successful application of our tunable half-life extension through diverse albumin binders and conjugation chemistries will be disclosed.

Ride of a lifetime: a novel half-life extension technology succeeding across chemical space

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.