posted on 2023-12-01, 11:29authored byHongxiang Zhu, Haoju Hua, Yanzhen Dong, Jinhua Zhang, Hongjiang Xu, Xingfeng Ge, Qin Lu, Jun Feng
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.