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Open AccessArticle

The Minimal Effect of Linker Length for Fatty Acid Conjugation to a Small Protein on the Serum Half-Life Extension

by Jinhwan Cho 1,†, Junyong Park 2,†, Giyoong Tae 1, Mi Sun Jin 3 and Inchan Kwon 1,2,*
1
School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea
2
Department of Biomedical Science and Engineering, GIST, Gwangju 61005, Korea
3
School of Life Science, GIST, Gwangju 61005, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomedicines 2020, 8(5), 96; https://doi.org/10.3390/biomedicines8050096
Received: 9 April 2020 / Revised: 23 April 2020 / Accepted: 23 April 2020 / Published: 26 April 2020
Conjugation of serum albumin or one of its ligands (such as fatty acid) has been an effective strategy to prolong the serum half-lives of drugs via neonatal Fc receptor (FcRn)–mediated recycling of albumin. So far, fatty acid (FA) has been effective in prolonging the serum half-lives for therapeutic peptides and small proteins, but not for large therapeutic proteins. Very recently, it was reported a large protein conjugated to FA competes with the binding of FcRn with serum albumin, leading to limited serum half-life extension, because primary FA binding sites in serum albumin partially overlap with FcRn binding sites. In order to prevent such competition, longer linkers between FA and the large proteins were required. Herein, we hypothesized that small proteins do not cause substantial competition for FcRn binding to albumin, resulting in the extended serum half-life. Using a small protein (28 kDa), we investigated whether the intramolecular distance in FA-protein conjugate affects the FcRn binding with albumin and serum half-life using linkers with varying lengths. Unlike with the FA-conjugated large protein, all FA-conjugated small proteins with different linkers exhibited comparable the FcRn binding to albumin and extended serum half-life. View Full-Text
Keywords: serum half-life extension; fatty acid conjugation; FcRn-mediated recycling; serum albumin serum half-life extension; fatty acid conjugation; FcRn-mediated recycling; serum albumin
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Cho, J.; Park, J.; Tae, G.; Jin, M.S.; Kwon, I. The Minimal Effect of Linker Length for Fatty Acid Conjugation to a Small Protein on the Serum Half-Life Extension. Biomedicines 2020, 8, 96.

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