Structure-guided discovery of dual recognition chemibodies

Autor: Jennifer Dao, Erin F. DiMauro, Elizabeth M. Doherty, Jie Tang, Philip Tagari, Alan C. Cheng, Jing Ye, Les P. Miranda, Xiaoshan Min, Thomas Nixey, Zhulun Wang, Abhinav Luthra, Sheree Johnstone
Rok vydání: 2019
Předmět:
Zdroj: Acta Crystallographica Section A Foundations and Advances. 75:a220-a220
ISSN: 2053-2733
Popis: Small molecules and antibodies each have advantages and limitations as therapeutics. Here, we present for the first time to our knowledge, the structure-guided design of "chemibodies" as small molecule-antibody hybrids that offer dual recognition of a single target by both a small molecule and an antibody, using DPP-IV enzyme as a proof of concept study. Biochemical characterization demonstrates that the chemibodies present superior DPP-IV inhibition compared to either small molecule or antibody component alone. We validated our design by successfully solving a co-crystal structure of a chemibody in complex with DPP-IV, confirming specific binding of the small molecule portion at the interior catalytic site and the Fab portion at the protein surface. The discovery of chemibodies presents considerable potential for novel therapeutics that harness the power of both small molecule and antibody modalities to achieve superior specificity, potency, and pharmacokinetic properties.
Databáze: OpenAIRE