Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
J Med Chem. 2011 Jul 28;54(14):5195-204. doi: 10.1021/jm200461m. Epub 2011 Jun 30.
Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. A vaccine capable of blocking heroin's effects could provide a long-lasting and sustainable adjunct to heroin addiction therapy. Heroin, however, presents a particularly challenging immunotherapeutic target, as it is metabolized to multiple psychoactive molecules. To reconcile this dilemma, we examined the idea of a singular vaccine with the potential to display multiple drug-like antigens; thus two haptens were synthesized, one heroin-like and another morphine-like in chemical structure. A key feature in this approach is that immunopresentation with the heroin-like hapten is thought to be immunochemically dynamic such that multiple haptens are simultaneously presented to the immune system. We demonstrate the significance of this approach through the extremely rapid generation of robust polyclonal antibody titers with remarkable specificity. Importantly, both the antinociceptive effects of heroin and acquisition of heroin self-administration were blocked in rats vaccinated using the heroin-like hapten.
海洛因成瘾是一个广泛存在的问题,具有一系列破坏性的社会后果。一种能够阻断海洛因作用的疫苗,可以为海洛因成瘾治疗提供一种持久和可持续的辅助手段。然而,海洛因是一个特别具有挑战性的免疫治疗靶点,因为它会代谢成多种具有精神活性的分子。为了解决这一难题,我们研究了一种具有潜在能力的单一疫苗,可以显示多种类似药物的抗原;因此,我们合成了两种半抗原,一种在化学结构上类似于海洛因,另一种类似于吗啡。这种方法的一个关键特征是,与海洛因样半抗原的免疫呈递被认为是免疫化学动态的,即多个半抗原同时呈递给免疫系统。我们通过极其快速地产生具有显著特异性的强大多克隆抗体滴度来证明这种方法的重要性。重要的是,使用类似于海洛因的半抗原进行疫苗接种的大鼠,其海洛因的镇痛作用和海洛因自我给药的获得均被阻断。