Paris, 19 march 2010
Despite the major advances achieved in the control of HIV, this infection still causes millions of deaths each year. The search for new cellular targets for novel antiviral therapies remains an important challenge.
Researchers at the Institut de Biologie Structurale (CNRS /Université Joseph Fourier/CEA)(1) have been working on a receptor called DC-SIGN which is found on the surface of dendritic cells: immune cells which are present in contact zones with the exterior, such as the skin or mucous membranes, and the first sites to encounter pathogens. DC-SIGN is implicated in the initial phases of HIV infection and constitutes a potential therapeutic target that has not yet been exploited.
What is the role of DC-SIGN? Under normal circumstances, it captures pathogens by recognizing certain characteristic oligosaccharides present on their surface. The pathogens are then internalized by dendritic cells that degrade them and present the fragments at their surface. These cells then move to lymphoid tissues where they trigger an immune response by the body, i.e. the production of T lymphocytes that can fight the pathogen. As for HIV, it uses DC-SIGN to ensure its transmission in an intact form to the T lymphocytes that it will infect. In particular, it attacks CD4+ T lymphocytes (carrying a molecule called CD4 that is susceptible to HIV) which are the principal target used by the virus to ensure its spread.
The researchers have developed a compound that can inhibit the HIV transmission process to CD4+ T lymphocytes. This tetravalent compound, endowed with four functional groups that mimic the oligosaccharides of pathogens, is recognized by DC-SIGN, which thus prevents HIV from using the receptor to travel to the lymphoid tissues. It has some particularly interesting properties; e.g. high solubility in physiological media, negligible cytotoxicity (2) and a long-lasting effect (even after washing the cells, the inhibitory effect can persist for several hours). Furthermore, the simple structure of the compound means that its large-scale production could easily be envisaged.
Last but not least, DC-SIGN is also utilized by other pathogens to circumvent the immune system. The compound developed by the research team could also be used to inhibit infection by the hepatitis C, dengue, Ebola and SARS (3) viruses, the Mycobacterium tuberculosis bacterium (which causes tuberculosis) and a number of parasites. It may even prove to be more effective in these cases than with HIV. This compound could therefore be added to the list of antiviral compounds designed on the basis of oside structures that exist in nature, the glycomimetics, such as Tamiflu which is used to control seasonal influenza.
Its efficacy has been proven in vitro to prevent the transmission of HIV from one cell to another. The researchers have protected their compound with a patent filed jointly by CNRS and Université Joseph Fourrier. The next step is to perform tests in animal models. Until they find a partner, or themselves set up a structure that can manage these activities, the researchers are continuing to enhance the efficacy of their compound to render it more specific to DC-SIGN and increase its interaction with this receptor.
(1) In collaboration with Italian and Spanish researchers in the context of the European CARMUSYS Network
(2) Toxic to cells
(3) Severe acute respiratory syndrome
Inhibition of DC-SIGN Mediated HIV infection by a linear trimannoside mimic in tetravalent presentation. Sattin S, Daghetti A, Thépaut M, Berzi A, Sanchez-Navarro M, Tabarani G, Rojo J, Fieschi F, Clerici M, Bernardi A. (2010) ACS Chem Biol. DOI: 10.1021/cb900216e
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