Kilo-Scale GMP Synthesis of Renewable Semisynthetic Vaccine-Grade Squalene.
Kilo-Scale GMP Synthesis of Renewable Semisynthetic Vaccine-Grade Squalene.
复制标题
可再生半合成疫苗级角鲨烯的公斤级 GMP 合成。
DOI：
10.1021/acs.oprd.3c00300
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发表时间：
2023
影响因子：
3.4
通讯作者：
Lykins,WilliamR
中科院分区：
文献类型：
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作者：
Fisher,KarlJ;Shirtcliff,Laura;Buchanan,Greg;Thompson,AndrewW;Woolard,FrankX;LaMunyon,DonaldH;Marshall,JonathanL;Baranouskas,MayaB;Voelker,RodgerB;Lusk,JasonS;Wells,CharlesE;Mohamath,Raodoh;Kinsey,Robert;Lykins,WilliamR
自20世纪90年代以来，三萜角鲨烯（（6 E，10 E，14 E，18 E）-2，6，10，15，19，23-六甲基二十四碳-2，6，10，14，18，22-六烯，CAS 111-02-4）的乳液已被用作流感疫苗中的佐剂。传统上来源于鲨鱼肝油，鲨鱼的过度捕捞和随之而来的海洋鲨鱼种群的减少提出了疫苗解毒剂级角鲨烯的可持续性问题。我们报告了一种半合成角鲨烯的方法，该方法符合当前用于疫苗的药典规范，利用了现成的反式-β-法呢烯（（6 E）-7，11-二甲基-3-亚甲基-1，6，10-十二碳三烯，CAS 18794-84-8），通过酵母发酵工艺从可持续的甘蔗中生产。通过千级GMP合成验证了所提出的路线的可扩展性。我们还报告了合成的半合成角鲨烯用于疫苗佐剂制剂时的物理稳定性和生物活性的数据。
Emulsions of the triterpene squalene ((6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene, CAS 111-02-4) have been used as adjuvants in influenza vaccines since the 1990s. Traditionally sourced from shark liver oil, the overfishing of sharks and concomitant reduction in the oceanic shark population raise sustainability issues for a vaccine adjuvant-grade squalene. We report a semisynthetic route to squalene meeting current pharmacopeial specifications for use in vaccines that leverages the ready availability oftrans-β-farnesene ((6E)-7,11-dimethyl-3-methylene-1,6,10-dodecatriene, CAS 18794-84-8), manufactured from sustainable sugar cane via a yeast fermentation process. The scalability of the proposed route was verified by a kilo-scale GMP synthesis. We also report data demonstrating the synthesized semisynthetic squalene’s physical stability and biological activity when used in a vaccine adjuvant formulation.