Abstract
BackgroundLectins 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 FindingsSmall 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.ConclusionThese 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.
Highlights
The biological barriers between the site of drug action and drug delivery are becoming increasingly important for the development of effective and safe medicines as mentioned by Lehr et al and Bies et al [1,2]
Several cDNA clones encoding precursors of odorranalectin were cloned from a skin cDNA library of O. grahami
The structural organization of the precursor is quite similar to amphibian antimicrobial peptide precursors, comprising a signal peptide sequence, an N-terminal spacer peptide region containing several aspartic and glutamic acid residues, and the mature peptide at the C-terminus of the precursor
Summary
The biological barriers between the site of drug action and drug delivery are becoming increasingly important for the development of effective and safe medicines as mentioned by Lehr et al and Bies et al [1,2]. Being proteins or glycoproteins themselves, lectins bind to sugar-moieties of the cell membrane. Lectins have been focused upon for more than 20 years and are becoming excellent candidates for drug delivery and targeting [3,4]. Some of problems are associated with lectins because of their large molecular weights. Molecular weights of most lectins are more than 10 KDa that likely results in toxicity and immunogenicty [2,5]. These problems are probably overcome by small size lectins with high target specificity. 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
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