Final Report Summary - CARMUSYS (Carbohydrate multivalent systems as tools to study pathogen interaction with DC-SIGN)
The importance of glycosciences in the development of biology and medicine and the central role played by chemistry in this process has recently been pointed out by the European Science Foundation (ESF). In this context, a highly interdisciplinary group of scientists (synthetic chemists, computational chemists, biochemists, immunologists, microbiologists, etc.) has been assembled to create the initial training network (ITN) CARMUSYS. This network has been formed by 12 groups from seven different European countries including universities, research institutes, small and medium sized enterprises (SMEs), a hospital and a doctoral school. The network has recruited and trained 15 early staged researchers (ESRs) and experienced researchers (ERs) with 11 different nationalities. All ESRs were embarked in PhD programmes and most of them have already got or are close to obtain a PhD degree. A full training programme including regular meetings, secondments and six workshops open to external attendants have been organised. The webpage of CARMUSYS (see http://www.carmusys.iiq.csic.es) contains the information related to all partners, dissemination activities, workshops, etc.
The multidisciplinary project behind CARMUSYS has been focussed on the design and synthesis of carbohydrate multivalent systems to be used as tools to study the interaction between carbohydrates and dendritic cell-specific intercellular adhesion molecule three (ICAM-3) grabbing non-integrin (DC-SIGN), a C-type lectin implicated in the recognition of pathogens and in some of the earliest stages of the infection process. To approach this goal, five different work packages have been established including work in computational analysis of ligands, synthesis of ligands and multivalent scaffolds, evaluation of ligand interaction with lectins and finally evaluation of the biological activity of compounds in cellular assays. The studies carried out in CARMUSYS have provided a selection of accessible ligands (glycomimetics) that have been conjugated on different multivalent platforms to achieve an adequate presentation of these ligands to interact efficiently with the receptor DC-SIGN. Moreover, we have demonstrated the selectivity of these ligands for DC-SIGN against langerin, a critical point for the design of HIV antiviral compounds. The carbohydrate multivalent systems prepared have shown an activity as inhibitors in infection studies with IC50s in the low nanomolar to picomolar range.
These results provide very interesting tools to understand the role of carbohydrates in relevant biological processes. Moreover, these multivalent systems prepared in the CARMUSYS have demonstrated a potential application as antiviral compounds. These results have been published in high impact journals among them we would like to highlight the results recently published in Nature Communication (Renato Ribeiro-Viana, Macarena Sánchez-Navarro, Joanna Luczkowiak, Julia R. Koeppe, Rafael Delgado, Javier Rojo, Benjamin. G. Davis. Nat. Commun. 2012, 3, 1303 DOI: 10.1038/ncomms2302) which has attracted the interest of the mass media. Different articles in newspapers, interviews at the television (TV) and radio of the principal investigators of this research has recently appeared. This is a proof of the impact and the interest that this research carried out by the different teams in CARMUSYS has for the society.
In summary, the new tools prepared in the multidisciplinary framework of CARMUSYS present interesting antiviral activity and also they could afford new insights to unravel the complex mechanisms of the immune system where DC-SIGN is involved, thus opening a strategy to develop synthetic vaccines through the modulation of dendritic cells activity. Addressing problems related to pathogen infection and immune therapy for those cases without an available solution, such as human immunodeficiency virus (HIV), Ebola, etc. present a strong impact in health care. Also, the well-trained group of young scientists recruited by CARMUSYS who have received the skills and the maturity required to address scientific problems in the glycoscience field will be part of the future European scientists contributing to solve health problems that civil society will suffer in the future.
The multidisciplinary project behind CARMUSYS has been focussed on the design and synthesis of carbohydrate multivalent systems to be used as tools to study the interaction between carbohydrates and dendritic cell-specific intercellular adhesion molecule three (ICAM-3) grabbing non-integrin (DC-SIGN), a C-type lectin implicated in the recognition of pathogens and in some of the earliest stages of the infection process. To approach this goal, five different work packages have been established including work in computational analysis of ligands, synthesis of ligands and multivalent scaffolds, evaluation of ligand interaction with lectins and finally evaluation of the biological activity of compounds in cellular assays. The studies carried out in CARMUSYS have provided a selection of accessible ligands (glycomimetics) that have been conjugated on different multivalent platforms to achieve an adequate presentation of these ligands to interact efficiently with the receptor DC-SIGN. Moreover, we have demonstrated the selectivity of these ligands for DC-SIGN against langerin, a critical point for the design of HIV antiviral compounds. The carbohydrate multivalent systems prepared have shown an activity as inhibitors in infection studies with IC50s in the low nanomolar to picomolar range.
These results provide very interesting tools to understand the role of carbohydrates in relevant biological processes. Moreover, these multivalent systems prepared in the CARMUSYS have demonstrated a potential application as antiviral compounds. These results have been published in high impact journals among them we would like to highlight the results recently published in Nature Communication (Renato Ribeiro-Viana, Macarena Sánchez-Navarro, Joanna Luczkowiak, Julia R. Koeppe, Rafael Delgado, Javier Rojo, Benjamin. G. Davis. Nat. Commun. 2012, 3, 1303 DOI: 10.1038/ncomms2302) which has attracted the interest of the mass media. Different articles in newspapers, interviews at the television (TV) and radio of the principal investigators of this research has recently appeared. This is a proof of the impact and the interest that this research carried out by the different teams in CARMUSYS has for the society.
In summary, the new tools prepared in the multidisciplinary framework of CARMUSYS present interesting antiviral activity and also they could afford new insights to unravel the complex mechanisms of the immune system where DC-SIGN is involved, thus opening a strategy to develop synthetic vaccines through the modulation of dendritic cells activity. Addressing problems related to pathogen infection and immune therapy for those cases without an available solution, such as human immunodeficiency virus (HIV), Ebola, etc. present a strong impact in health care. Also, the well-trained group of young scientists recruited by CARMUSYS who have received the skills and the maturity required to address scientific problems in the glycoscience field will be part of the future European scientists contributing to solve health problems that civil society will suffer in the future.