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Mannosylated Lipopetides As Model Vaccines for Targeting the Mannose Receptor Bita Sedaghat Pharmacy Doctorate

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Mannosylated Lipopetides As Model Vaccines for Targeting the Mannose Receptor Bita Sedaghat Pharmacy Doctorate Mannosylated lipopetides as model vaccines for targeting the mannose receptor Bita Sedaghat Pharmacy Doctorate A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2016 School of Chemistry and Molecular Biosciences Abstract The mannose receptor (MR) is an important component of the immune system and understanding the structural and conformational characteristics of this receptor is a key aspect of targeted vaccine design. Improved understanding of the role of carbohydrate recognition domains (CRDs) 4-7 in recognising glycosylated ligands present on the surface of pathogens such as C. albicans, P. carinii, L. donovani, and M. tuberculosis has given new insight into MR vaccine development. Initial studies identified mannan and its derivatives to be important ligands in MR targeting, providing essential knowledge about structural properties of the MR. During the last 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-labelled mannosylated + lipid dendrimers that contained the ovalbumin CD4 epitope, OVA323-339, as the model peptide antigen were synthesised 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 antigen presenting cells. Mannosylated building blocks were prepared with a Lewis acid reaction and the reaction was successfully modified and monitored for a better yield. This was followed by solid phase synthesis of mannosylated peptides with an azide functional group and a fluorescent tag. Considering the presence of multi-components on the designed mannosylated peptide, different methods of preparation was used and a high yield of the final mannosylated peptides with an azide functional group and a fluorescent tag were prepared. Further, OVA323-339 lipopeptides with an alkyne functional group were prepared using microwave assisted peptide synthesis. Final vaccine structures were prepared by attaching azide and alkyne functional groups using click chemistry. The same methods were applied for the preparation of a library of control vaccine structures. In vitro uptake studies performed on macrophage (F4/80+) and dendritic (CD11c+) cells showed significant uptake and/or binding for vaccine constructs containing mannose and lipid, and also for the lipopeptide vaccine construct without mannose when compared to the controls (containing no lipid, no mannose and no mannose or lipid). Further, in vitro mannan competition assays demonstrated that uptake of the mannosylated and lipidated vaccine constructs was MR mediated. To address the specificity of receptor uptake, surface plasmon resonance (SPR) was performed using Biacore technology which confirmed a high affinity of the mannosylated and lipidated vaccine constructs towards the human recombinant MR in vitro when compared with vaccine constructs without mannose. These studies also confirmed that both mannose and lipid moieties play significant i roles in receptor-mediated uptake on APCs, potentially facilitating vaccine development. SPR methods were modified for a better quality of study. In vivo studies with the aim of understanding immune modulatory effects of the mannose and lipid moieties in relation to the structural properties were performed. There have been many studies indicating the ability of the MR in linking the innate immunity (short-term immune response through macrophages and DCs) to adaptive immunity (long-term response by T cell activation and antibody response). This linkage is due to the MR mediated endocytosis of macrophages and dendritic cells (cells of innate immunity) and then antigen presentation to the T cells which isresponsible for a long- term adoptive response. However, it has not been completely disclosed whether uptake by the MR can induce the desired pathways involved in T cell activation. In this study, OT-II T cells were isolated from OT-II transgenic mice (B6.Cg-Tg[TcraTcrb]425Cbn/J) and were adoptively transferred to C57BL/6 mice. Adoptively transferred OT-II cell proliferation was shown to be unaffected by mannosylated lipopetide vaccine constructs. However, antigen specific cytokine release studies done by cytokine bead array and intra cellular staining, showed a relationship between the structural properties and the selection of specific T helper pathways (Th1 and Th2). Here, presence of both mannose and lipid activated cytokines (IL-4, IL-5, IL-13) related to Th2 pathway. On the other hand, the presence of lipid alone on the vaccine structures activated inflammatory cytokines (IL-2 and IFN- ) that are related to the Th1 pathway. Here, it was also found that structural differences between the vaccine constructs including length of spacers between mannosyl moieties and presence of lipid could affect the levels of cytokine release. Structural differences were also responsible for selective action towards a Th pathway. For instance, two spacers on the vaccine structures with both mannose and lipid were more selective towards the Th2 response, while presence of lipid alone was able to act towards the Th1 pathway. In these studies a positive control group, ovalbumin 323-339 sequence mixed with cholera toxin (OVA+ CT), was used. Here, OVA+ CT, structures with mannose only and structures without mannose and lipid were not significant in the Th1 and Th2 cytokine activation pathways. Finally, antibody measurements following three time vaccinations showed a lack of antibody response against the vaccine constructs and their control groups. Overall, the results suggested activation of APCs by vaccine constructs that was not strong enough to activate a T cell or B cell response but could activate cytokine release. Mannosylation has been shown to be an effective tool for antigen delivery to the immune system. There are studies that have indicated that mannosylation activates pathways to which the immune system does not react and recognises the antigens as self-antigens. This finding could mean an exciting future for vaccine and drug delivery and has to be further investigated. II Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. III Publications during candidature i. Peer-reviewed papers Sedaghat, B., Stephenson, R., and Toth, I., (2014) Targeting the Mannose Receptor with Mannosylated Subunit Vaccines. Curr Med Chem. 21 (30):3405-18 Sedaghat, B., Stephenson, R. J., Giddam, A., Eskandari, S., Apte, S. H., Pattinson, D. J., Doolan, D. L., and Toth, I. (2016) Synthesis of mannosylated lipopeptides with receptor targeting properties. Bioconjugate chemistry. 27 (3), 533-548 ii. Conferences abstract Oral presentations Bita Sedaghat, Rachel J. Stephenson, Ashwini Kumar Giddam, Sharareh Eskandari, Simon Apte, David Pattinson, Denise Doolan, and Istvan Toth, Binding and immune modulation properties of mannosylated lipo-peptide vaccines, Vaccine and vaccination Asia pacific Global summit, July 27- 29, 2015 Brisbane, Australia Bita Sedaghat, Rachel J. Stephenson, Ashwini Kumar Giddam, Sharareh Eskandari, Simon Apte, David Pattinson, Denise Doolan, and Istvan Toth, Mannosylated lipopeptides with receptor targeting properties, School of Chemistry and Molecular Biosciences Symposium, November 18th, 2014, Brisbane, Australia Bita Sedaghat, Rachel J. Stephenson, Ashwini Kumar Giddam, Sharareh Eskandari, Simon Apte, David Pattinson, Denise Doolan, and Istvan Toth, Targeting ability and immune modulatory effects of synthetic mannosylated lipopetide vaccines, School of Chemistry and Molecular Biosciences Symposium, November 26th, 2015, Brisbane, Australia iii. Poster Presentations B. Sedaghat, R. Stephenson, I. Toth, Syntheis of mannosylated lipopeptides as targets for the mannose receptor, Control Release Society (CRS), 2013, Sydney, Australia B. Sedaghat,
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