Cyclic adenosine 5′-diphosphate ribose analogs without a southern ribose inhibit ADP-ribosyl cyclase-hydrolase CD38

Joanna M. Swarbrick, Richard Graeff, Hongmin Zhang, Mark P. Thomas, Quan Hao, Barry V L Potter

Research output: Contribution to journalArticle

12 Citations (Scopus)
95 Downloads (Pure)

Abstract

Cyclic adenosine 5′-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5′-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective N1-ribosylation. Replacing the base N9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the nonessential nature of the southern ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs, and 8-amino-N9-butyl-cIDPR is comparable to the best noncovalent CD38 inhibitors to date (IC50 = 3.3 μM). Crystallographic analysis of the shCD38:8-amino-N9-butyl-cIDPR complex to a 2.05 Å resolution unexpectedly reveals an N1-hydrolyzed ligand in the active site, suggesting that it is the N6-imino form of cADPR that is hydrolyzed by CD38. While HPLC studies confirm ligand cleavage at very high protein concentrations, they indicate that hydrolysis does not occur under physiological concentrations. Taken together, these analogs confirm that the "northern" ribose is critical for CD38 activity and inhibition, provide new insight into the mechanism of cADPR hydrolysis by CD38, and may aid future inhibitor design.

Original languageEnglish
Pages (from-to)8517-8529
Number of pages13
JournalJournal of Medicinal Chemistry
Volume57
Issue number20
Early online date16 Sep 2014
DOIs
Publication statusPublished - 23 Oct 2014

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