Inhibitors of DC-SIGN receptor
DC-SIGN is a C-type lectin receptor present on the surface of dendritic cells. It binds to carbohydrate structures found on the surface of a number of pathogens: viruses (HIV, ebola, cytomegalovirus), bacteria (M. tuberculosis, S. pneumoniae), fungi (C. albicans), and parasites (Leishmana). The surface of these pathogens is typically rich in mannose and fucose. Upon binding, DC-SIGN can mediate uptake of the pathogen into the dendritic cell and launch immune response. Hence, DC-SIGN inhibitors could act as anti-infective agents and also as probes to study in detail the mechanism of function of this receptor.
The affinity of monovalent carbohydrates to DC-SIGN is typically very weak (dissociation constants are in the mM range). Nature overcomes this problem by multivalency – complex oligo and polysaccharides bind to multimeric receptors. Due to their high polarity and tedious synthesis, carbohydrates are not very promissing therapeutic leads. Recent studies have shown that apart from the primary carbohydrate binding site, DC-SIGN displays five secondary binding sites, available to accommodate small drug-like molecules (Figure 1).
Figure 1. DC-SIGN receptor, primary carbohydrate binding site (yellow) and secondary binding sites I–V. Picture taken from literature .
Fragment-based drug discovery (FBDD) is a drug discovery method which relies on the screening of small molecule fragments (150–300 Da) with the target receptor. Because of their low molecular weight, fragment hits typically bind only weakly, but their binding affinity may be increased by fragment growing or fragment linking. A library of almost 1 000 fragments was screened for interaction with DC-SIGN and several hits were found to interact with three secondary binding sites.
1. Mannose-based DC-SIGN inhibitors
The aim of this project is to link D-mannose with one or two fragments known to interact with the secondary binding sites (Figure 2a). The mannose moiety is expected to function as anchor directing the fragment to the protein and improving its affinity.
2. Fragment linking
We are working on the synthesis of several fragments found to interact with DC-SIGN. Subsequently, we are linking these fragments to obtain larger molecules with improved drug-like properties and higher affinity towards DC-SIGN (Figure 2b).
3. New bicyclic heterocyclic fragments
Since several of the fragment hits are bicyclic heterocyclic compounds, we are synthesizing a small library of related compounds for structure–activity relationship (SAR) studies (Figure 2c).
Figure 2. Overview of the target compounds. a) Mannose-based DC-SIGN inhibitors; b) DC-SIGN inhibitors created by fragment linking; c) new bicyclic heterocyclic fragments.
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