SAMs can be used to target Siglecs and modulate Siglec-expressing cells by modifying the sialic acid backbone at various positions, from C-2 to C-9. The carboxylic acid, however, must be left intact. The first attempts were made to develop high-affinity sialic acid mimetics for Siglec-2, which led to the discovery that increased binding affinity came hydrogen bonding and lipophilic interactions between SAMs and Siglec-2. Several separate modifications have been made at the C-2, C-5 and C-9 positions, leading Mesch et al. to hypothesizing that the simultaneous modification at all three positions could lead to optimization of binding.