Synthesis of Mannosylated Lipopeptides with Receptor Targeting Properties

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• 作者：Bita Sedaghat ; Rachel J. Stephenson ; Ashwini Kumar Giddam ; Sharareh Eskandari ; Simon H. Apte ; David J. Pattinson ; Denise L. Doolan ; Istvan Toth
• 刊名：Bioconjugate Chemistry
• 出版年：2016
• 出版时间：March 16, 2016
• 年：2016
• 卷：27
• 期：3
• 页码：533-548
• 全文大小：831K
• ISSN：1520-4812

文摘

Present on the surface of antigen presenting cells (APCs), the mannose receptor (MR) has long been recognized as a front-line receptor in pathogen recognition. During the past decade many attempts have been made to target this receptor for applications including vaccine and drug development. In the present study, a library of vaccine constructs comprising fluorescently labeled mannosylated lipid-dendrimers that contained the ovalbumin CD4⁺ epitope, OVA_323–339, as the model peptide antigen were synthesized using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in APCs. Uptake studies performed on F4/80⁺ and CD11c⁺ cells showed significant uptake and/or binding for lipopeptides containing mannose, and also the lipopeptide without mannose when compared to the control peptides (peptide with no lipid and peptide with no mannose and no lipid). Furthermore, mannan inhibition assays demonstrated that uptake of the mannosylated and lipidated peptides was receptor mediated. To address the specificity of receptor uptake, surface plasmon resonance studies were performed using biacore technology and confirmed high affinity of the mannosylated and lipidated vaccine constructs toward the MR. These studies confirm that both mannose and lipid moieties play significant roles in receptor-mediated uptake on APCs, potentially facilitating vaccine development.