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Structure-guided Discovery of Dual-recognition Chemibodies. | LitMetric

Structure-guided Discovery of Dual-recognition Chemibodies.

Sci Rep

Department of Therapeutic Discovery, Amgen Discovery Research, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA, 94080, USA.

Published: May 2018

AI Article Synopsis

Article Abstract

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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954141PMC
http://dx.doi.org/10.1038/s41598-018-25848-0DOI Listing

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