Synthesis of mannosylated lipopeptides with receptor targeting properties

Sedaghat, Bita, Stephenson, Rachel J., Giddam, Ashwini Kumar, Eskandari, Sharareh, Apte, Simon H., Pattinson, David, Doolan, Denise L., and Toth, Istvan (2016) Synthesis of mannosylated lipopeptides with receptor targeting properties. Bioconjugate Chemistry, 27 (3). pp. 533-548.

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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.

Item ID: 46658
Item Type: Article (Research - C1)
ISSN: 1043-1802
Funders: National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC APP1037304
Date Deposited: 14 Dec 2016 02:11
FoR Codes: 42 HEALTH SCIENCES > 4206 Public health > 420699 Public health not elsewhere classified @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320404 Cellular immunology @ 25%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320405 Humoural immunology and immunochemistry @ 25%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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