Long-Term Strategies for Poorly Water-Soluble Peptides: Combining Fatty Acid Modification with PAS Fusion

化学 脂肪酸 生物化学 胆汁酸 乙型肝炎病毒 病毒 病毒学 生物
作者
Hongxiang Zhu,Haoju Hua,Yanzhen Dong,Jinhua Zhang,Hongjiang Xu,Xingfeng Ge,Qin Lu,Jun Feng
出处
期刊:Bioconjugate Chemistry [American Chemical Society]
卷期号:34 (12): 2366-2374 被引量:1
标识
DOI:10.1021/acs.bioconjchem.3c00464
摘要

Bulevirtide, an entry inhibitor for the hepatitis B virus (HBV) and hepatitis D virus (HDV), is currently available on the European market. However, its clinical application is constrained by its short half-life and poor water solubility, rendering it unsuitable for fatty acid modification, aimed at achieving long-term effects. To address this limitation, we integrated a polypeptide chain consisting of Pro, Ala, and Ser at the C-terminus, which increased its hydrophilicity. To obtain the fusion sequence of A1 and A2, encompassing amino acids 1–47 of Bulevirtide and PAS, we used Escherichia coli fermentation expression. Subsequently, the N-terminal myristoyl groups of A1 and A2 were modified to yield Myr-A1 and Myr-A2, respectively. Five fatty acid moieties with the same hydrophilic spacers and different fatty acids were conjugated to analogs, generating 10 bioconjugations. The bioconjugates were then evaluated for their anti-HBV activity. Among them, HB-10 was selected for pharmacokinetic analysis and demonstrated a significantly prolonged half-life, with 5.88- and 13.18-fold increases in beagle dogs and rats, respectively. Additionally, higher drug doses resulted in substantially elevated liver concentrations. In conclusion, via fatty acid incorporation and PASylation, we successfully developed a novel Bulevirtide bioconjugate, HB-10, that exhibits an extended action duration. This compound holds substantial promise as a prospective long-acting entry inhibitor, warranting further investigation.
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