Sulfonate-isosteric replacement examined within heroin-hapten vaccine design.
Sulfonate-isosteric replacement examined within heroin-hapten vaccine design.
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DOI：
10.1016/j.bmcl.2020.127388
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发表时间：
2020-09
影响因子：
2.7
通讯作者：
T. Belz;Paul T. Bremer;Bin Zhou;Steven Blake;Beverly Ellis;L. M. Eubanks;K. Janda
中科院分区：
文献类型：
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作者：
T. Belz;Paul T. Bremer;Bin Zhou;Steven Blake;Beverly Ellis;L. M. Eubanks;K. Janda
海洛因过量和成瘾仍然是当今世界重大的健康和经济负担，每年造成数十亿美元的损失。此外，治疗海洛因成瘾的药物选择有限。在我们努力消除海洛因成瘾所构成的公共健康威胁的过程中，我们研制了针对海洛因的疫苗。为了扩展我们现有的海洛因疫苗库，我们合成了新的芳基和烷基磺酸酯半抗原;即芳基单磺酸酯（HMsAc）和芳基/烷基二磺酸酯（H（Ds）2）作为海洛因的羧基电子等排体，然后通过疫苗接种研究将它们与我们的模型海洛因半抗原（HAc）进行比较。将海洛因半抗原与载体蛋白CRM 197偶联，并将所得CRM-免疫偶联物用于按照已建立的免疫方案接种Swiss韦伯斯特小鼠。结合研究表明，HMsAc疫苗产生的抗海洛因抗体亲和力最高，其次分别是HAc和H（Ds）2疫苗（HMsAc> HAc> HDs 2）。然而，与HAcvaccine相比，HMsAcnor H（Ds）2疫苗都不能产生针对精神活性代谢物6-乙酰吗啡（6-AM）的高亲和力抗体。血脑生物分布研究支持这些结合结果，疫苗效率遵循HAc> HMsAc> HMsH（Ds）2的趋势。本文所述的工作提供了对疫苗药物设计中半抗原等排置换的使用的了解。
Heroin overdose and addiction remain significant health and economic burdens in the world today costing billions of dollars annually. Moreover, only limited pharmacotherapeutic options are available for treatment of heroin addiction. In our efforts to combat the public health threat posed by heroin addiction, we have developed vaccines against heroin. To expand upon our existing heroin-vaccine arsenal, we synthesized new aryl and alkyl sulfonate ester haptens; namely aryl-mono-sulfonate (HMsAc) and Aryl/alkyl-di-sulfonate (H(Ds)2) as carboxyl-isosteres of heroin then compared them to our model heroin-hapten (HAc) through vaccination studies. Heroin haptens were conjugated to the carrier protein CRM197and the resulting CRM-immunoconjugates were used to vaccinate Swiss Webster mice following an established immunization protocol. Binding studies revealed that the highest affinity anti-heroin antibodies were generated by the HMsAcvaccine followed by the HAcand H(Ds)2vaccines, respectively (HMsAc> HAc≫HDs2). However, neither the HMsAcnor H(Ds)2vaccines were able to generate high affinity antibodies to the psychoactive metabolite 6-acetyl morphine (6-AM), in comparison to the HAcvaccine. Blood brain bio-distribution studies supported these binding results with vaccine efficiency following the trend HAc> HMsAc≫ H(Ds)2The work described herein provides insight into the use of hapten-isosteric replacement in vaccine drug design.