Sanderson Sam D, Cheruku Srinivasa R, Padmanilayam Maniyan P, Vennerstrom Jonathan L, Thiele Geoffrey M, Palmatier Matthew I, Bevins Rick A
School of Allied Health Professions, University of Nebraska Medical Center, 985155 Nebraska Medical Center, Omaha, NE 68198-5155, USA.
Int Immunopharmacol. 2003 Jan;3(1):137-46. doi: 10.1016/s1567-5769(02)00260-6.
This paper describes the synthesis of a nicotine hapten (Nic) that possesses a carboxyl sidearm functional group allowing for conjugation to a peptide via amide bond formation. Nic was attached to the N-terminal amino group of a 19-residue peptide composed of a conformationally biased agonist of human C5a (YSFKPMPLaR), which is used as a molecular adjuvant and a B cell epitope of human MUC1 glycoprotein (YKQGGFLGL) to yield a peptide-based nicotine vaccine, NicYKQGGFLGLYSFKPMPLaR. Rats immunized with this vaccine were significantly less sensitive to behavioral effects (a Pavlovian discrimination task) induced by their exposure to high concentrations of nicotine (0.4 mg/kg) relative to their non-vaccinated counterparts. The attenuation of these nicotine-induced behavioral effects emanated from the presence of nicotine-specific antibodies (Abs) that were present in the sera of vaccinated rats even after their repeated exposure to high concentrations of nicotine during the time required to perform the behavioral assays. These results suggest that immunization with NicYKQGGFLGLYSFKPMPLaR in the absence of adjuvant is an effective means of inducing a nicotine-specific Ab response, which is capable of attenuating nicotine-induced behavioral/psychoactive effects.
本文描述了一种尼古丁半抗原（Nic）的合成，该半抗原具有一个羧基侧链官能团，可通过酰胺键形成与肽进行偶联。Nic连接到由人C5a的构象偏向激动剂（YSFKPMPLaR）组成的19个残基肽的N端氨基上，该肽用作分子佐剂和人MUC1糖蛋白的B细胞表位（YKQGGFLGL），从而产生一种基于肽的尼古丁疫苗，即NicYKQGGFLGLYSFKPMPLaR。与未接种疫苗的大鼠相比，用该疫苗免疫的大鼠对高浓度尼古丁（0.4mg/kg）暴露所诱导的行为效应（巴甫洛夫辨别任务）的敏感性显著降低。这些尼古丁诱导的行为效应的减弱源于尼古丁特异性抗体（Abs）的存在，即使在行为测定所需时间内反复暴露于高浓度尼古丁后，接种疫苗大鼠的血清中仍存在这些抗体。这些结果表明，在无佐剂情况下用NicYKQGGFLGLYSFKPMPLaR进行免疫是诱导尼古丁特异性抗体反应的有效手段，该反应能够减弱尼古丁诱导的行为/精神活性效应。
