Design and Synthesis of DC-SIGN Antagonists

DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule 3-Grabbing Nonintegrin), a specific C-type lectin recognizing pathogen-cell surface glycoproteins, is probably the first trans-membrane receptor on immature dendritic cells (DC) which encounters invading pathogens and binds a number of diverse pathogen-associated molecular patterns. Normally, this binding event triggers internalization of the DC-SIGN-pathogen complex followed by lysosomal degradation of the pathogen and conjugation of the resulting fragments with MHC-II to initiate an adaptive immune response from T cells. Some pathogens, however, have been reported to take advantage of this mechanism, as they appear to deter DC maturation through DC-SIGN-mediated signalling and inhibit antigen presentation to T cells. In particular, van Kooyk’s group has shown that HIV-1 enters DC via DC-SIGN avoiding lytic degradation [1]. By doing so, HIV-1 not only escapes the host immune system, but also is presented directly to T cells, which enables fully disseminated HIV-1 infection. Inhibition of pathogen interaction using DC-SIGN specific antagonists is considered as a plausible concept for the development of novel anti-infective agents. Several groups have recently demonstrated that inhibition of DC-SIGN, either by designed glycoconjugates or by antibodies, prevents pathogen attachment to DC and inhibits the infection of other immune cells at its earliest steps [2,3]. Our group has been active in this area and, in collaboration with the European network Carmusys [4], has developed two groups of mannose-based and fucose-based glycomimetic ligands that inhibit DC-SIGN mediated HIV infection in cellular and tissue models. The presentation will deal with the design and synthesis of these molecules, as well as on the structural studies detailing their interaction with the target lectin. [1] Y. van Kooyk, T.B.H. Geijtenbeek Nat Rev Immunol, 3, 2003, 697. [2] B. Ernst, J.L. Magnani Nat Rev Drug Discov 8, 2009, 661 and references therein [3] S. Sattin, A. Daghetti, M. Thépaut, A. Berzi, M. Sánchez-Navarro, G. Tabarani, J. Rojo, F. Fieschi, M. Clerici, A. Bernardi ACS Chem Biol 5, 2010, 301 and references therein. [4] http://www.carmusys.iiq.csic.es/