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CC BY 4.0 · Pharmaceutical Fronts 2025; 07(02): e126-e136
DOI: 10.1055/a-2594-1472
Original Article

Cost-Effective Synthesis of Bule-OH: An Alternative to Bulevirtide for Hepatitis B and D Research

Hongxiang Zhu
1   China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Haoju Hua
1   China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Yuanzhen Dong
1   China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   Shanghai Duomirui Biotechnology Co., Ltd., Shanghai, People's Republic of China
,
Hongjiang Xu
3   Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, People's Republic of China
,
Jun Feng
1   China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
› Author Affiliations
Funding None.
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Abstract

Bulevirtide is a hepatitis B virus/hepatitis D virus (HDV) entry inhibitor that has been commercially available in Europe. It is manufactured via solid-phase synthesis of 47 amino acids with N-terminal myristoylation on MBHA resin. This production method presents significant environmental and economic challenges that limit the accessibility for patients. This study aims to develop a more sustainable and cost-efficient alternative through the rational design of Bule-OH, a Bulevirtide analogue featuring C-terminal carboxyl modification, rather than Bulevirtide's C-terminal amide. In this work, Bule-OH is successfully synthesized by combining fermentation expression with chemical modification techniques to reduce production costs. Bule-OH has a carboxylic acid group at the C-terminus, whereas Bulevirtide has an amide. We compared the pharmacological profiles of Bule-OH and Bulevirtide by determining their functional performance, including activity and enzymatic stability; and biophysical properties, including stability and self-association assays, followed by their pharmacokinetic evaluation in hNTCP (human sodium taurocholate cotransporting polypeptide) mice model of HDV infection. The results showed that the pharmacokinetic characteristics of Bule-OH and Bulevirtide in the target organ, the liver, were similar, whereas Bule-OH had a stronger liver targeting ability. These findings suggest that Bule-OH has the potential to be an economical and efficient alternative to Bulevirtide.

Keywords

Bulevirtide - Bule-OH - production costs - pharmacokinetic

Ethical Approval

The in vivo pharmacokinetic experiments were reviewed and approved by the Ethical Committee of Experimental Animals at the Chia Tai Tianqing Pharmaceutical Group.


Supplementary Material



Publication History

Received: 17 February 2025

Accepted: 24 April 2025

Article published online:
19 May 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

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