Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Cessation Therapeutics LLC, 3031 Tisch Way Ste 505, San Jose, California 95128, United States.
J Am Chem Soc. 2020 Aug 5;142(31):13294-13298. doi: 10.1021/jacs.0c05219. Epub 2020 Jul 27.
The United States is in the midst of an unprecedented epidemic of opioid substance use disorder, and while pharmacotherapies including opioid agonists and antagonists have shown success, they can be inadequate and frequently result in high recidivism. With these challenges facing opioid use disorder treatments immunopharmacotherapy is being explored as an alternative therapy option and is based upon antibody-opioid sequestering to block brain entry. Development of a heroin vaccine has become a major research focal point; however, producing an efficient vaccine against heroin has been particularly challenging because of the need to generate not only a potent immune response but one against heroin and its multiple psychoactive molecules. In this study, we explored the consequence of regioselective deuteration of a heroin hapten and its impact upon the immune response against heroin and its psychoactive metabolites. Deuterium (H) and cognate protium heroin (H) haptens were compared head to head in an inclusive vaccine study. Strikingly the H vaccine granted greater efficacy in blunting heroin analgesia in murine behavioral models compared to the H vaccine. Binding studies confirmed that the H vaccine elicited both greater quantities and equivalent or higher affinity antibodies toward heroin and 6-AM. Blood-brain biodistribution experiments corroborated these affinity tests. These findings suggest that regioselective hapten deuteration could be useful for the resurrection of previous drug of abuse vaccines that have met limited success in the past.
美国正处于阿片类药物物质使用障碍的空前流行之中，尽管包括阿片类激动剂和拮抗剂在内的药物疗法已经显示出成功，但它们可能不够充分，并且经常导致高复发率。鉴于阿片类药物使用障碍治疗面临这些挑战，免疫药理学正在被探索作为一种替代治疗选择，它基于抗体-阿片类物质的隔离以阻止大脑进入。海洛因疫苗的开发已成为一个主要的研究重点；然而，由于不仅需要产生强大的免疫反应，而且需要针对海洛因及其多种精神活性分子产生免疫反应，因此针对海洛因开发有效的疫苗一直具有特别的挑战性。在这项研究中，我们探讨了海洛因半抗原的区域选择性氘化的后果及其对海洛因及其精神活性代谢物的免疫反应的影响。氘（H）和同源的氕海洛因（H）半抗原在一个包容性疫苗研究中进行了直接比较。令人惊讶的是，与 H 疫苗相比，H 疫苗在小鼠行为模型中对海洛因镇痛作用的抑制效果更好。结合研究证实，H 疫苗引起了对海洛因和 6-AM 的抗体数量更大、亲和力相同或更高。血液-大脑生物分布实验证实了这些亲和力测试。这些发现表明，区域选择性半抗原氘化可能有助于复活过去在过去取得有限成功的先前药物滥用疫苗。
