DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule 3-Grabbing Nonintegrin), a specific C-type lectin recognizing pathogen-cell surface glycoproteins, is a trans-membrane receptor on immature dendritic cells (DC) which binds a number of 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. 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. Our group has been active in this area and, in collaboration with the European network Carmusys (http://www.carmusys.iiq.csic.es/) has developed 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 the glycomimetic monovalent ligands, the process of structural optimization which allowed us to build affinity and selectivity in their structure, the synthesis and optimization of polyvalent constructs that allowed us to achieve high affinity interaction with the lectin.
|Titolo:||Towards the development of selective glycomimetic antagonists of DC-SIGN|
|Data di pubblicazione:||mag-2013|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||Towards the development of selective glycomimetic antagonists of DC-SIGN / A. Bernardi. ((Intervento presentato al convegno Meeting of the Hungarian Carbohydrate Group tenutosi a Mátrafüred nel 2013.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|