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PLoS ONE:药用两栖动物最轻的凝集素分子

来源:生物谷 2008-06-13 13:33

生物谷报道:中科院昆明动物研究所、复旦大学以及中国科学院上海药物研究所组成的研究团队从药用两栖动物中发现了目前世界上分子量最小的凝集素,其很可能成为药物靶向输送载体中起导向作用的功能性分子。

药物靶向输送和定位是世界研究的热点。定向输送药物到特定的发病部位(病灶)将极大地提高药物利用效率和减少副作用。凝集素具有专一的糖基结合特性,生物体不同的器官与组织含有不同的糖基,因此凝集素可以专一地与不同的器官或组织相结合。由于凝集素的器官与组织结合专一性,它们一直被认为是最好的药物靶向输送和定位载体而受到药物学家的青睐。几十年来,科研人员一直在寻找合适的凝集素药物输送载体分子,但遗憾的是,绝大部分已知的凝集素分子量都大于10000,大分子量凝集素作为药物靶向输送和定位载体将可能导致毒性和免疫原性等严重副作用。小分子量凝集素将克服这些缺陷而作为理想的药物输送载体分子。

以上科研团队协作从药用两栖动物中发现了一分子量仅为1700的多肽凝集素,可以专一地与岩藻糖结合,体内专一地结合于肝和肺,且无毒性和具极低的免疫原性。此外,该多肽凝集素由分子内二硫键形成环状结构使其在生物体内不易受到蛋白酶水解而具有较好的稳定性,在小鼠体内半衰期>5小时。这些特性使该多肽凝集素成为优秀的药物靶向输送和定位候选载体分子。以上研究结果发表于4月11日《公共科学图书馆·综合》。(生物谷www.bioon.com

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PLoS ONE,doi:10.1371/journal.pone.0002381,Jianxu Li, Huw H. Rees

Odorranalectin Is a Small Peptide Lectin with Potential for Drug Delivery and Targeting

Jianxu Li1,5#, Hongbing Wu2#, Jing Hong3,5#, Xueqing Xu1,5, Hailong Yang1, Bingxian Wu2, Yipeng Wang1,5, Jianhua Zhu2, Ren Lai1*, Xinguo Jiang2*, Donghai Lin3*, Mark C. Prescott4, Huw H. Rees4

1 Biotoxin Units of Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming Yunnan, China2 School of Pharmacy, Fudan University, Shanghai, China3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China4 School of Biological Sciences University of Liverpool, Liverpool, United Kingdom5 Graduate School of the Chinese Academy of Sciences, Beijing, China

Abstract

Background

Lectins are sugar-binding proteins that specifically recognize sugar complexes. Based on the specificity of protein–sugar interactions, different lectins could be used as carrier molecules to target drugs specifically to different cells which express different glycan arrays. In spite of lectin's interesting biological potential for drug targeting and delivery, a potential disadvantage of natural lectins may be large size molecules that results in immunogenicity and toxicity. Smaller peptides which can mimic the function of lectins are promising candidates for drug targeting.

Principal Findings

Small peptide with lectin-like behavior was screened from amphibian skin secretions and its structure and function were studied by NMR, NMR-titration, SPR and mutant analysis. A lectin-like peptide named odorranalectin was identified from skin secretions of Odorrana grahami. It was composed of 17 aa with a sequence of YASPKCFRYPNGVLACT. L-fucose could specifically inhibit the haemagglutination induced by odorranalectin. 125I-odorranalectin was stable in mice plasma. In experimental mouse models, odorranalectin was proved to mainly conjugate to liver, spleen and lung after i.v. administration. Odorranalectin showed extremely low toxicity and immunogenicity in mice. The small size and single disulfide bridge of odorranalectin make it easy to manipulate for developing as a drug targeting system. The cyclic peptide of odorranalectin disclosed by solution NMR study adopts a β-turn conformation stabilized by one intramolecular disulfide bond between Cys6-Cys16 and three hydrogen bonds between Phe7-Ala15, Tyr9-Val13, Tyr9-Gly12. Residues K5, C6, F7, C16 and T17 consist of the binding site of L-fucose on odorranalectin determined by NMR titration and mutant analysis. The structure of odorranalectin in bound form is more stable than in free form.

Conclusion

These findings identify the smallest lectin so far, and show the application potential of odorranalectin for drug delivery and targeting. It also disclosed a new strategy of amphibian anti-infection.

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