Targeting L-SIGN: a potential tool against SARS-CoV-2

The C-type lectin receptors (CLRs) DC-SIGN and L-SIGN are known to interact with surface glycoproteins of many pathogens, thus inducing activation of the initial stages of the adaptive immune response. Nevertheless, several deadly viruses - such as HIV, Ebola, hepatitis C viruses - have developed strategies to subvert the natural role of CLRs and use them to promote virus internalization and dissemination. The recent discovery that also SARS-CoV-2 can exploit DC and L-SIGN to adhere to the host and enhance its infection, has stimulated the development of antagonists for these receptors and in particular against L-SIGN, which is co-expressed with the viral entry receptor ACE2 in the lungs and in endothelia. However, designing selective L-SIGN ligands is extremely challenging, due to the very high similarity of the two lectins (ca. 80% homology). We have recently reported the first class of highly selective L-SIGN ligands, whose structure relies on a mannose scaffold modified at position 2 with a methylene guanidine triazole. The first member of this class, Man84, displays 50-fold selectivity for L-SIGN against DC-SIGN. Inspired by this molecule, we here present a new set of glycomimetics, able to keep and, in some cases, improve the aforementioned selectivity. All the designed antagonists are based on a mono-mannose scaffold, modified at position 2 with a triazole moiety, decorated with a guanidinium isosteric group. Their synthesis and biological activity will be described and the structure-activity relationship (SAR) of the isosters’ set will be discussed.