E- and P-selectin : differences and similarities guide the development of novel selectin antagonists

Selectins, namely E-, P-, and L-selectin, are carbohydrate-recognizing proteins that mediate the initial step of leukocyte recruitment to sites of inflammation. This vital process can turn deleterious in case of acute and chronic states of inflammation like stroke, reperfusion injury, and psoriasis or rheumatoid arthritis, respectively. In addition, cancer cells have been shown to exploit this selectin mediated pathway to metastasize. Blocking of the selectins is consequently considered a promising therapeutic approach.
The tetrasaccharide sialyl Lewisx (sLex) was identified as the minimum binding epitope of all three selectins and became the lead structure for various drug discovery programs. SLex itself suffers from the typical downsides of carbohydrate leads, namely complex structure and synthesis, and poor pharmacokinetic and pharmacodynamic properties, which impede the development of selectin antagonists. The rational design of antagonists is furthermore hampered by the lack of information on the thermodynamics of the selectin-ligand interactions. However, these information are of vital importance for successful lead optimization.
Inter alia, this thesis addresses these major issues in the design of glycomimetic selectin antagonists.
A fast and efficient synthetic route to the D-GlcNAc mimic (1R,2R,3S)-3-methylcyclohexane-1,2-diol was developed, which allows the multigram scale synthesis of this key intermediate (chapter 2.2.).
Similarities and differences between E- and P-selectin were exploited to develop less polar, structurally simplified P- and E-selectin antagonists with increased binding affinity compared to sLex (chapter 2.3.).
A series of glycomimetic amides and sulfonamides was developed to target a hitherto unexplored binding pocket of P-selectin. The structurally simplified, and non-charged mimetics exhibited up to threefold higher binding affinities than sLex (chapter 2.4.).
A synthetic route to derivatives of 2,2-dialkyl-2-O-glycosyl glycolic acid was developed and the resulting glycomimetics were tested as E-selectin antagonists (chapter 2.5).
Thermodynamic binding parameters of sLex and E-selectin antagonists were analyzed. It was found that a combination of reduced polarity of weakly binding residues and enhanced pre-organization is the key to overcome enthalpy entropy compensation (chapter 2.6.).
Literature known antagonists were synthesized to evaluate their potential in established in-house assays (chapter 2.7.).