Sugar mimetics in  α-galactosylceramide analogues: Potent immunostimulating agents via iNKT activation   — ASN Events
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  3. Sugar mimetics in  α-galactosylceramide analogues: Potent immunostimulating agents via iNKT activation  

Sugar mimetics in  α-galactosylceramide analogues: Potent immunostimulating agents via iNKT activation   (#89)

Amadeu Llebaria 1 , Roser Borràs 1 , Youssef Harrak 1 , Lorena Usero 2 , Hui-Fern Koay 3 4 , Daniel Pellicci 3 4 , Jerome Le Nours 5 6 , Rhys Price 5 6 , Tang Yongqing 5 6 , Ana Sánchez 2 , Dale I. Godfrey 3 4 , Jamie Rossjohn 5 6 , Carme Roura-Mir 2
  1. IQAC-CSIC, Barcelona, Spain
  2. Cellular Immunology Lab, Institut de Biotecnologia I Biomedicina, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain
  3. Dept. of Microbiology and Immunology , Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia
  4. ARC Center of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Australia
  5. Dept. of Biochemistry and Molecular Biology, School of Biomedicical Sciences, Monash University, Clayton, Australia
  6. ARC Centre of Excellence in Advanced Molecular Imaging, Monash University , Clayton, Australia

The design and synthesis of aminocyclitol moiety with control of sterochemistry and the attachment to phytoceramide backbone results in several analogues of α-galactosylceramide (aGalCer) [1, 2], a potent glycolipid antigen acting on invariant Natural Killer T (iNKT) cells, binding to the CD1d protein in presenting cells and being recognized by iNKT TCR. iNKT cells are a unique subtype of T lymphocytes expressing surface markers either of T-cells (TCR) and Natural Killer (NK1.1 in mouse and CD161 in human) cells, this singular combination of properties confer to iNKT the capability to act either in innate or adaptive immune responses. They are believed to be involved in several diseases such as type I diabetes, asthma, allergy or cancer among others. The activation of iNKT cells by aGalCer triggers a strong release of cytokines without selectivity between Th1 or Th2 response, and in some cases, after a first administration induces iNKT cells anergy. These limitations, together with the promising role of iNKT as immunotherapeutic tool, stimulate the search of new analogues with improved biological profiles, constituting an interesting and challenging research objective. Our aminocyclitol-ceramide analogues and some new structural concepts introduced have led to potent activity in vitro and in vivo. Moreover, structural studies on CD1d-Ag-TCR complex point out a binding mode similar to that of aGalCer [3, 4].

 

 

[1] Harrak, Y.; et al. ChemMedChem 2009, 4, 1608.

[2] Harrak, Y.; et al. Journal of the American Chemical Society 2011, 133, 12079.

[3] Patel, O.; et al. The Journal of Immunology 2011, 187, 4705.

[4] Kerzerho, J.; et al. The Journal of Immunology 2012, 188, 2254.