Subtype-selectivity of metal-dependent methionine aminopeptidase inhibitors

Altmeyer, Markus; Marschner, Aline; Schiffmann, Rolf; Klein, Christian D.

doi:10.1016/j.bmcl.2010.05.093

Cited by 22 publications

(21 citation statements)

References 17 publications

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“…Although some 8-HQ-based inhibitors of metalloproteins have been reported [31][32][33][34][35][36], little information is available concerning their inhibitory activities against dinuclear Zn 2? enzymes.…”

Section: Introductionmentioning

confidence: 99%

Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn2+ fluorophores, kinetic, and X-ray crystallographic study

et al. 2012

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The selective inhibition of an aminopeptidase from Aeromonas proteolytica (AAP), a dinuclear Zn(2+) hydrolase, by 8-quinolinol (8-hydroxyquinoline, 8-HQ) derivatives is reported. We previously reported on the preparation of 8-HQ-pendant cyclens as Zn(2+) fluorophores (cyclen is 1,4,7,10-tetraazacyclododecane), in which the nitrogen and phenolate of the 8-HQ units (as well as the four nitrogens of cyclen) bind to Zn(2+) in a bidentate manner to form very stable Zn(2+) complexes at neutral pH (K (d) = 8-50 fM at pH 7.4). On the basis of this finding, it was hypothesized that 8-HQ derivatives have the potential to function as specific inhibitors of Zn(2+) enzymes, especially dinuclear Zn(2+) hydrolases. Assays of 8-HQ derivatives as inhibitors were performed against commercially available dinuclear Zn(2+) enzymes such as AAP and alkaline phosphatase. 8-HQ and the 5-substituted 8-HQ derivatives were found to be competitive inhibitors of AAP with inhibition constants of 0.16-29 μM at pH 8.0. The nitrogen at the 1-position and the hydroxide at the 8-position of 8-HQ were found to be essential for the inhibition of AAP. Fluorescence titrations of these drugs with AAP and an X-ray crystal structure analysis of an AAP-8-HQ complex (1.3-Å resolution) confirmed that 8-HQ binds to AAP in the "Pyr-out" mode, in which the hydroxide anion of 8-HQ bridges two Zn(2+) ions (Zn1 and Zn2) in the active site of AAP and the nitrogen atom of 8-HQ coordinates to Zn1 (Protein Data Bank code 3VH9).

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Section: Introductionmentioning

confidence: 99%

Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn2+ fluorophores, kinetic, and X-ray crystallographic study

et al. 2012

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“…Other low MWt compounds, comprising sulfonamide derivatives closely related to the compounds reported below, have been reviewed by Altmeyer et al [120].…”

Section: Methionine Aminopeptidase 2 Inhibitorsmentioning

confidence: 97%

New Perspectives on the Development of Antiobesity Drugs

Costantino

Barlocco

2015

Future Med. Chem.

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After many years of research, obesity is still a disease with an unmet medical need. Very few compounds have been approved, acting mainly on neuromediators; researches, in recent years, pointed toward compounds potentially safer than first-generation antiobesity drugs, able to interact with one or more (multitarget therapy) receptors for substances produced by the gut, adipose tissue and other targets outside CNS. Other holistic approaches, such as those involving gut microbiota and plant extracts, appeared recently in the literature, and undoubtedly will contribute to the discovery of a valuable therapy for this disease. This review deals with the positive results and the pitfalls obtained following these approaches, with a view on their clinical trial studies.

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“…The compounds are of the general structure shown above where R 1 and R 2 are generally H, Alkyl, Cl, F, NH 2 , CN, NO 2 or phenyl ketones [30,31]. Of these possible derivatives, compound ( 13 ) was the most active compound exhibiting activity better than that of the parent compound 2-(2-pyridyl)benzimidazole (R 1 = R 2 = H) with IC 50 values of 0.162 and 0.574 μM, respectively, against Ec MetAP1 with Co(II) cofactors [31].…”

Section: Classes Of Metap Inhibitorsmentioning

confidence: 99%

“…For other azabenzimidazole derivatives (2-(2-pyridine)-5-azabenzimidazole, 2-(2-pyridine)-4,6-diazaben-zimidazole and 2-(2-pyridine)-4,7-diazabenzimidazole) the increase in activity is to a lesser extent, although all exhibit better activity than the benzimidazole parent compound. Concerning selectivity, compounds ( 13 ) and ( 14 ) were co-screened against Hs MetAP types 1 and 2 and were found to be more potent against the bacterial enzyme than both human enzymes (( 13 ), IC 50 = 28.8 μM, Hs MetAP1; ( 14 ), IC 50 = 27.6 and 26.7 μM, Hs MetAP 1 and 2, respectively, Co(II) cofactors) [30]. …”

Section: Classes Of Metap Inhibitorsmentioning

confidence: 99%

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Advances in Bacterial Methionine Aminopeptidase Inhibition

Helgren¹,

Wangtrakuldee²,

Staker³

et al. 2015

CTMC

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Methionine aminopeptidases (MetAPs) are metalloenzymes that cleave the N-terminal methionine from newly synthesized peptides and proteins. These MetAP enzymes are present in bacteria, and knockout experiments have shown that MetAP activity is essential for cell life, suggesting that MetAPs are good antibacterial drug targets. MetAP enzymes are also present in the human host and selectivity is essential. There have been significant structural biology efforts and over 65 protein crystal structures of bacterial MetAPs are deposited into the PDB. This review highlights the available crystallographic data for bacterial MetAPs. Structural comparison of bacterial MetAPs with human MetAPs highlights differences that can lead to selectivity. In addition, this review includes the chemical diversity of molecules that bind and inhibit the bacterial MetAP enzymes. Analysis of the structural biology and chemical space of known bacterial MetAP inhibitors leads to a greater understanding of this antibacterial target and the likely development of potential antibacterial agents.

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Subtype-selectivity of metal-dependent methionine aminopeptidase inhibitors

Cited by 22 publications

References 17 publications

Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn2+ fluorophores, kinetic, and X-ray crystallographic study

Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn2+ fluorophores, kinetic, and X-ray crystallographic study

New Perspectives on the Development of Antiobesity Drugs

Advances in Bacterial Methionine Aminopeptidase Inhibition

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