American Chemical Society
jm1c00032_si_001.pdf (1.03 MB)

Exendin 4‑Hapten Conjugate Capable of Binding with Endogenous Antibodies for Peptide Half-life Extension and Exerting Long-Acting Hypoglycemic Activity

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journal contribution
posted on 2021-04-07, 16:05 authored by Shijie Dai, Haofei Hong, Kun Zhou, Kai Zhao, Yuntian Xie, Chen Li, Jie Shi, Zhifang Zhou, Lei Nie, Zhimeng Wu
Hapten-specific endogenous antibodies are naturally occurring antibodies present in human blood. Herein, we investigated a new strategy in which small-molecule haptens were utilized as naturally occurring antibody binders for peptide half-life extension. The glucagon-like peptide 1 receptor agonist exendin 4 was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus via sortase A-mediated ligation. The resulting Ex4–DNP conjugates retained GLP-1 receptor activation potency in vitro and had a similar in vivo acute glucose-lowering effect comparable to that of native Ex4. Pharmacokinetic studies and hypoglycemic duration tests demonstrated that the Ex4–DNP conjugates displayed significantly elongated half-lives and improved long-acting antidiabetic activity in the presence of endogenous anti-DNP antibodies. In chronic treatment studies, once-daily administration of optimal conjugate 7 demonstrated more beneficial effects without prominent toxicity compared with Ex4. This strategy provides a new approach and represents an alternative to the well-established peptide-Fc fusion strategy to improve the peptide half-life and the therapeutic efficacy.