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Synthesis and immunological effects of C14-linked 4,5-epoxymorphinan analogues as novel heroin vaccine haptens
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2021-4-19 , DOI: 10.1039/d1cb00029b Eugene S Gutman 1 , Thomas C Irvin 1 , J Brian Morgan 1 , Rodell C Barrientos 2, 3 , Oscar B Torres 2, 3 , Zoltan Beck 2, 3 , Gary R Matyas 2 , Arthur E Jacobson 1 , Kenner C Rice 1
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2021-4-19 , DOI: 10.1039/d1cb00029b Eugene S Gutman 1 , Thomas C Irvin 1 , J Brian Morgan 1 , Rodell C Barrientos 2, 3 , Oscar B Torres 2, 3 , Zoltan Beck 2, 3 , Gary R Matyas 2 , Arthur E Jacobson 1 , Kenner C Rice 1
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Active immunization is being explored as a potential therapeutic to combat accidental overdose and to mitigate the abuse potential of opioids. Hapten design is one of the crucial factors that determines the efficacy of a candidate vaccine to substance abuse and remains one of the most active areas of research in vaccine development. Herein we report for the first time the synthesis of three novel opiate surrogates with the linker attachment site at C14, 1 (6,14-AmidoHap), 2 (14-AmidoMorHap), and 3 (14-AmidoHerHap) as novel heroin haptens. The compounds 1, 2, and 3 are analogues with different substituents at C6: an acetamide, a hydroxyl moiety, and an acetate, respectively. All three haptens had a phenolic hydroxyl group at C3. The haptens were conjugated to the tetanus toxoid carrier protein, adjuvanted with liposomal monophosphoryl lipid A/aluminum hydroxide and were tested in mice in terms of immunogenicity and efficacy. Immunization of mice resulted in antibody endpoint titers of >105 against all the haptens. Neither of the conjugates of 1, 2, and 3 had induced antibodies with selectivity broad enough to recognize and bind heroin, 6-AM, and morphine resulting in little to no protection against the antinociceptive effects of heroin in vivo. Only the mice immunized with conjugate 3 were partially protected against heroin-induced antinociception. These results contribute to the growing body of knowledge that the linker position and the subtle structural differences in the hapten scaffold impact the selectivity of the induced antibodies. Together, these highlight the importance of rational hapten design for heroin vaccine development.
中文翻译：
C14-连接的 4,5-环氧吗啡喃类似物作为新型海洛因疫苗半抗原的合成和免疫学效应
正在探索主动免疫作为一种潜在的治疗方法，以对抗意外过量服用和减轻阿片类药物滥用的可能性。半抗原设计是决定候选疫苗对药物滥用功效的关键因素之一，并且仍然是疫苗开发中最活跃的研究领域之一。本文我们报告首次三种新型阿片的合成与接头附着位点在C14，替代物1（6,14-AmidoHap），2（14-AmidoMorHap），和3（14-AmidoHerHap）作为新的半抗原海洛因。化合物1、2和3是在 C6 上具有不同取代基的类似物：分别是乙酰胺、羟基部分和乙酸酯。所有三种半抗原在 C3 处都具有酚羟基。半抗原与破伤风类毒素载体蛋白结合，辅以脂质体单磷酰脂质 A/氢氧化铝，并在小鼠中测试免疫原性和功效。小鼠的免疫导致针对所有半抗原的抗体终点滴度>10 5。既不的缀合物的1，2，和3种已诱导的抗体具有选择性的足够广泛的识别和结合海洛因，6-AM，并导致小对抗海洛因的镇痛作用没有保护吗啡体内. 只有用偶联物3免疫的小鼠才能部分保护免受海洛因诱导的镇痛作用。这些结果有助于越来越多的知识，即接头位置和半抗原支架中的细微结构差异会影响诱导抗体的选择性。总之，这些突出了合理的半抗原设计对海洛因疫苗开发的重要性。
更新日期：2021-04-19
中文翻译：
C14-连接的 4,5-环氧吗啡喃类似物作为新型海洛因疫苗半抗原的合成和免疫学效应
正在探索主动免疫作为一种潜在的治疗方法，以对抗意外过量服用和减轻阿片类药物滥用的可能性。半抗原设计是决定候选疫苗对药物滥用功效的关键因素之一，并且仍然是疫苗开发中最活跃的研究领域之一。本文我们报告首次三种新型阿片的合成与接头附着位点在C14，替代物1（6,14-AmidoHap），2（14-AmidoMorHap），和3（14-AmidoHerHap）作为新的半抗原海洛因。化合物1、2和3是在 C6 上具有不同取代基的类似物：分别是乙酰胺、羟基部分和乙酸酯。所有三种半抗原在 C3 处都具有酚羟基。半抗原与破伤风类毒素载体蛋白结合，辅以脂质体单磷酰脂质 A/氢氧化铝，并在小鼠中测试免疫原性和功效。小鼠的免疫导致针对所有半抗原的抗体终点滴度>10 5。既不的缀合物的1，2，和3种已诱导的抗体具有选择性的足够广泛的识别和结合海洛因，6-AM，并导致小对抗海洛因的镇痛作用没有保护吗啡体内. 只有用偶联物3免疫的小鼠才能部分保护免受海洛因诱导的镇痛作用。这些结果有助于越来越多的知识，即接头位置和半抗原支架中的细微结构差异会影响诱导抗体的选择性。总之，这些突出了合理的半抗原设计对海洛因疫苗开发的重要性。
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