Reference : Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound l...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/24707
Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
English
Minond, D. [The Scripps Research Institute > Lead Identification, Translational Research Institute > > >]
Saldanha, S. A. [The Scripps Research Institute > Lead Identification, Translational Research Institute > > >]
Spaargaren, M. [The Scripps Research Institute > Lead Identification, Translational Research Institute > > >]
Spicer, T. [The Scripps Research Institute > Lead Identification, Translational Research Institute > > >]
Fotsing, J. R. [The Scripps Research Institute > Department of Chemistry > > >]
Weide, T. [The Scripps Research Institute > Department of Chemistry > > >]
Fokin, V. V. [The Scripps Research Institute > Department of Chemistry > > >]
Sharpless, K. B. [The Scripps Research Institute > Department of Chemistry and the Skaggs Institute for Chemical Biology > > >]
Galleni, Moreno mailto [Université de Liège - ULg > Département des sciences de la vie > Macromolécules biologiques >]
Bebrone, Carine mailto [Université de Liège - ULg > > Centre d'ingénierie des protéines >]
Lassaux, Patricia mailto [Université de Liège - ULg > > > Doct. sc. (bioch., bioch. mol.&cell., bioinf.&mod.-Bologne)]
Hodder, P. [The Scripps Research Institute > Lead Identification, Translational Research Institute/ Department of Molecular Therapeutics > > >]
15-Jul-2009
Bioorganic & Medicinal Chemistry
Elsevier Science
17
5027-37
Yes (verified by ORBi)
International
0968-0896
1464-3391
Oxford
United Kingdom
[en] metallo-beta-lactamase ; inhibitor
[en] VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area of active research, an array of potent, small molecule inhibitors is yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused 'click' chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine K(i) and mechanism of enzyme inhibition. As a result, two previously described pharmacologic agents, mitoxantrone (1,4-dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (K(i)=K(i)(')=1.5+/-0.2microM) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzenesulfonamide (1, K(i)=0.41+/-0.03microM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, K(i)=1.4+/-0.10microM). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing Escherichia coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays.
http://hdl.handle.net/2268/24707
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TF8-4WKH6GJ-1&_user=532038&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000026659&_version=1&_urlVersion=0&_userid=532038&md5=4fcf2da02739f09a726dac7058ecf12c
We acknowledge Elsevier

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