Peptides and proteins offer a natural entity to tackle high value medicinal targets.  However, native  biologics oftentimes have a short half-life which makes translation to patients extremely difficult, if not next to impossible.  We have addressed this longstanding challenge by developing novel site-selective protein chemistry methods to install a proprietary half-life extension technology. Discovery of a histidine-directed modification enables N-terminal site-selective labeling of proteins and peptides.  Transglutaminase mediated chemoenzymatic labeling of lysines allows for site-specific conjugation to peptides, proteins, and antibodies.  To address the specific challenge of rapid clearance, we identified a novel albumin binding fatty acid with ~ 50 fold greater affinity than native myristic acid. Further SAR through biacore binding resulted in an optimized lipid extending the half-life of proteins and peptides to that of albumin. In applying these technologies to the extremely short acting serelaxin peptide, we show that this long acting conjugate analog extends the exposure and shows dose responsive target engagement towards a goal for improved treatment for heart failure. Utilizing our newly developed toolbox of technologies, we have prolonged the pharmacokinetic and pharmacodynamic profile of a diverse set of macromolecules and provided a potential path forward toward developable biotherapeutics of the future. <br/> <br/>

Tuning macromolecular fate through site-selective chemical conjugation of a novel half-life extender

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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