Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues

Riccardo Petrelli, Yuk Yin Sham, Liqiang Chen, Krzysztof Felczak, Eric Bennett, Daniel Wilson, Courtney Aldrich, Jose S. Yu, Loredana Cappellacci, Palmarisa Franchetti, Mario Grifantini, Francesca Mazzola, Michele Di Stefano, Giulio Magni, Krzysztof W. Pankiewicz

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC50 = 110 μM and IC50 = 87 μM, respectively) and Mycobacterium tuberculosis NAD kinase (IC50 = 80 μM and IC50 = 45 μM, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC50 = 6 μM) and mycobacterium NAD kinase (IC50 = 14-19 μΜ reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation.

Original languageEnglish (US)
Pages (from-to)5656-5664
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number15
DOIs
StatePublished - Aug 1 2009

Bibliographical note

Funding Information:
These studies were funded by the Center for Drug Design, University of Minnesota.

Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.

Keywords

  • Dithioadenosine analogues, NAD conformation
  • Enzyme inhibition
  • NAD kinase
  • NADP
  • Tiazofurin

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