DC-SIGN Antagonists, a Potential New Class of Anti-Infectives

Abstract

DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a type II C-type lectin that functions as an adhesion molecule located on dendritic cells (DCs). It enables some of the functions of DCs, including migration, pathogen recognition, internalisation and processing, and their binding to T cells. HIV-1 has been reported to enter DCs by being bound to DC-SIGN, escaping the normal lytic pathway in DCs' endosomes and avoiding the immune system defence system. A very similar mechanism of survival has been observed for some other pathogens. This makes DC-SIGN a receptor of interest in the design of distinctive anti-infectives that would inhibit DC-SIGN-pathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DC-SIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DCSIGN binds mannose- and fucose-based oligo- and polysaccharides, their structural mimics have been designed and proved to inhibit pathogen-DC-SIGN interaction. Furthermore, recent in vitro studies have demonstrated that DC-SIGN antagonists block effectively the transmission of pathogens like HIV-1 and Ebola to CD4+ T cells. Although DC-SIGN has not been validated in vivo as a druggable target yet, we await future DC-SIGN antagonists as a new and highly promising group of novel anti-infectives.

A multivalent inhibitor of the DC-SIGN dependent uptake of HIV-1 and Dengue virus

“…The competition experiment was performed using 25 mM Tris-HCl pH 8, 150 mM NaCl, 4 mM (1) (2) where R hi and R lo are maximum and minimum asymptotes, A 1 is an inflection point and A 2 is a slope of the curve.…”

“…This observation has turned DC-SIGN into an interesting target for the design of anti-viral agents. [2][3][4][5][6][7][8][9][10] The task is complicated by the presence of other C-type lectins of similar selectivity, like Langerin, [11] that has a protective effect against HIV infection. Thus, selective DC-SIGN ligands that interact only weakly with Langerin are actively sought after as potentially useful therapeutic tools against HIV and other viruses that use DC-SIGN as a primary receptor.…”

DC-SIGN Antagonists – A Paradigm of C-Type Lectin Binding Inhibition

“…DC-SIGN antagonists work by inhibiting pathogen interaction with DC-SIGN, so the very first phase of pathogen infection can be inhibited, as proven in in vitro experiments [10,41,42]. DC-SIGN antagonists may be designed as monovalent glycomimetics based on the DC-SIGN-binding oligosaccharides and their multimeric presentation [43]. Alternatively, screening of compound libraries has been successful in obtaining non-carbohydrate DC-SIGN antagonists [44].…”

“…In the case of HIV-1, the major initial contact site between HIV-1 and DC-SIGN is in the vaginal mucosa, so a DC-SIGN antagonist could be administered topically to prevent HIV-1 transmission without systemic application [45]. It has to be stressed that no clinically proven therapy based on inhibition of DC-SIGNmediated pathogen infection has been presented [43].…”

Broad Antiviral Activity of Carbohydrate-Binding Agents Against Dengue Virus Infection

“…But caution must be taken into account as the DC-SIGN receptor has also an important role in the activation of protective immune responses instead of promoting the viral dissemination. However, several DC-SIGN antagonists have been developed such as small interfering RNAs (siRNA) silencing DC-SIGN expression [55], specific anti-DC-SIGN antibodies [56] and glycomimetics interacting with DC-SIGN [57]. The in vivo effects of DC-SIGN antagonists remain to be elucidated.…”