Nicotinamide adenine dinucleotide (NAD+) is well-known for its function as a redox co-enzyme and as the source for the formation of adenosine diphosphate ribose (ADPr) polymers in a post-translational modification called ADP-ribosylation. However, several decades ago, NAD+ was also found to be the substrate of transmembrane protein cluster of differentiation 38 (CD38) . Located on the cellular membrane of immune cells, CD38 mainly hydrolyzes NAD+ resulting in ADPr but can also facilitate cyclization to produce cyclic ADPr. The former reaction is suggested to regulate the ADP-ribosylation of cell surface proteins, while the latter product acts as secondary messenger in a signaling pathway that affects the intracellular Ca2+ flux . Crystallographic studies on human CD38 indicated that the intermediate of the enzymatic hydrolysis is substrate dependent and can be both covalent and non-covalent . For the non-covalent intermediate, an oxocarbenium ion is formed and stabilized by hydrogen bonding interactions. On the contrary, a stable covalent intermediate can arise when the anomeric center of the ribose is targeted by glutamic acid residue 226 in the active site.
This study is focused on the synthesis of an NAD+ analogue containing a cyclic sulfate warhead that can trap the nucleophilic amino acid residue, thus covalently and irreversibly inhibiting CD38 (Figure 1A). Further implementation of the warhead into an activity-based probe (ABP) would allow screening of compound libraries to find novel inhibitors for CD38 (Figure 1B).
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