Department of Chemistry, Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Chemistry, Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, The Scripps Research Institute, La Jolla, CA 92037, USA.
Bioorg Med Chem. 2019 Jan 1;27(1):125-132. doi: 10.1016/j.bmc.2018.11.027. Epub 2018 Nov 20.
Heroin is a highly abused opioid that has reached epidemic status within the United States. Yet, existing therapies to treat addiction are inadequate and frequently result into rates of high recidivism. Vaccination against heroin offers a promising alternative therapeutic option but requires further development to enhance the vaccine's performance. Hsp70 is a conserved protein with known immunomodulatory properties and is considered an excellent immunodominant antigen. Within an antidrug vaccine context, we envisioned Hsp70 as a potential dual carrier-adjuvant, wherein immunogenicity would be increased by co-localization of adjuvant and antigenic drug hapten. Recombinant Mycobacterium tuberculosis Hsp70 was appended with heroin haptens and the resulting immunoconjugate granted anti-heroin antibody production and blunted heroin-induced antinociception. Moreover, Hsp70 as a carrier protein surpassed our benchmark Her-KLH cocktail through antibody-mediated blockade of 6-acetylmorphine, the main mediator of heroin's psychoactivity. The work presents a new avenue for exploration in the use of hapten-Hsp70 conjugates to elicit anti-drug immune responses.
海洛因是一种高度滥用的阿片类药物，已在美国达到流行程度。然而，现有的治疗成瘾的方法并不充分，并且经常导致高复发率。针对海洛因的疫苗接种提供了一种有前途的替代治疗选择，但需要进一步开发以增强疫苗的性能。Hsp70 是一种保守的蛋白质，具有已知的免疫调节特性，被认为是一种极好的免疫显性抗原。在抗毒品疫苗的背景下，我们将 Hsp70 视为一种潜在的双重载体-佐剂，其中通过佐剂和抗原性药物半抗原的共定位来增加免疫原性。重组结核分枝杆菌 Hsp70 与海洛因半抗原缀合，所得免疫缀合物产生抗海洛因抗体并减弱海洛因引起的镇痛作用。此外，Hsp70 作为载体蛋白通过抗体介导的 6-乙酰吗啡阻断作用超过了我们的 Her-KLH 鸡尾酒的基准，6-乙酰吗啡是海洛因精神活性的主要介质。这项工作为使用半抗原-Hsp70 缀合物引发抗毒品免疫反应提供了一个新的探索途径。
