Site-Specific Lipidation of a Small-Sized Protein Binder Enhances the Antitumor Activity through Extended Blood Half-Life

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Protein and peptide therapeutics tend to have a short blood circulation time mainly caused by rapid clearance in kidney, leading to a low therapeutic efficacy. Here, we demonstrate that the antitumor activity of a small-sized protein binder can be significantly enhanced by prolonged blood half-life through site-specific lipidation. An unnatural amino acid was genetically incorporated into a specific site with the highest accessibility in a human interleukin-6 (IL-6)-targeting protein binder with a size of 30.8 kDa, followed by conjugation with palmitic acid using cooper-free click chemistry. The resulting protein binder was shown to have a binding capacity for serum albumin, maintaining a comparable binding affinity for human IL-6 to the native protein binder. The terminal half-life of the lipidated protein binder was estimated to be 10.7 h, whereas the native one had a half-life of 20 min, resulting in a significantly enhanced tumor suppression effect. The present approach can be generally applied to small-sized therapeutic proteins for the elongation of circulation time and increase of bioavailability in blood, consequently enhancing their therapeutic efficacy.
Publisher
AMER CHEMICAL SOC
Issue Date
2020-08
Language
English
Article Type
Article
Citation

ACS OMEGA, v.5, no.31, pp.19778 - 19784

ISSN
2470-1343
DOI
10.1021/acsomega.0c02555
URI
http://hdl.handle.net/10203/276396
Appears in Collection
BS-Journal Papers(저널논문)
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