当前位置: X-MOL 学术Mol. Pharmaceutics › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Novel Vaccine That Blunts Fentanyl Effects and Sequesters Ultrapotent Fentanyl Analogues.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-07-30 , DOI: 10.1021/acs.molpharmaceut.0c00497
Rodell C Barrientos 1, 2 , Eric W Bow 3 , Connor Whalen 1 , Oscar B Torres 1, 2 , Agnieszka Sulima 3 , Zoltan Beck 1, 2 , Arthur E Jacobson 3 , Kenner C Rice 3 , Gary R Matyas 1
Affiliation  

Active immunization is an emerging potential modality to combat fatal overdose amid the opioid epidemic. In this study, we described the design, synthesis, formulation, and animal testing of an efficacious vaccine against fentanyl. The vaccine formulation is composed of a novel fentanyl hapten conjugated to tetanus toxoid (TT) and adjuvanted with liposomes containing monophosphoryl lipid A adsorbed on aluminum hydroxide. The linker and hapten N-phenyl-N-(1-(4-(3-(tritylthio)propanamido)phenethyl)piperidin-4-yl)propionamide were conjugated sequentially to TT using amine-N-hydroxysuccinimide-ester and thiol–maleimide reaction chemistries, respectively. Conjugation was facile, efficient, and reproducible with a protein recovery of >98% and a hapten density of 30–35 per carrier protein molecule. In mice, immunization induced high and robust antibody endpoint titers in the order of >106 against the hapten. The antisera bound fentanyl, carfentanil, cyclopropyl fentanyl, para-fluorofentanyl, and furanyl fentanyl in vitro with antibody-drug dissociation constants in the range of 0.36–4.66 nM. No cross-reactivity to naloxone, naltrexone, methadone, or buprenorphine was observed. In vivo, immunization shifted the antinociceptive dose–response curve of fentanyl to higher doses. Collectively, these preclinical results showcased the desired traits of a potential vaccine against fentanyl and demonstrated the feasibility of immunization to combat fentanyl-induced effects.

中文翻译:

新颖的疫苗能减弱芬太尼的作用,并隔离超强效的芬太尼类似物。

主动免疫是对抗阿片类药物流行中致命过量用药的新兴潜在方式。在这项研究中,我们描述了抗芬太尼有效疫苗的设计,合成,配方和动物试验。该疫苗制剂由与破伤风类毒素(TT)缀合并与含有吸附在氢氧化铝上的单磷酰脂质A的脂质体佐剂的新型芬太尼半抗原组成。使用胺-N将接头和半抗原N-苯基-N-(1-(4-(3-(三(三苯甲硫基)丙酰胺基)苯乙基)哌啶-4-基)丙酰胺顺序偶联到TT-羟基琥珀酰亚胺酯和硫醇-马来酰亚胺的化学反应。结合容易,高效且可重现,每个载体蛋白分子的蛋白回收率> 98%,半抗原密度为30-35。在小鼠中,免疫诱导的针对半抗原的抗体终点效价高而稳健,大于10 6在体外,抗血清结合芬太尼,芬太尼,环丙基芬太尼,氟芬太尼和呋喃基芬太尼的抗体-药物解离常数范围为0.36-4.66 nM。没有观察到与纳洛酮,纳曲酮,美沙酮或丁丙诺啡的交叉反应。体内免疫将芬太尼的抗伤害感受剂量反应曲线转移到更高剂量。总的来说,这些临床前结果显示了潜在的抗芬太尼疫苗的所需特性,并证明了进行免疫以对抗芬太尼诱导的作用的可行性。
更新日期:2020-09-09
down
wechat
bug