X‐ray crystal structures of an orally available aminopeptidase inhibitor, <scp>T</scp>osedostat, bound to anti‐malarial drug targets <scp>P</scp>f<scp>A</scp>‐<scp>M</scp>1 and <scp>P</scp>f<scp>A</scp>‐<scp>M</scp>17

Drinkwater, N.; Bamert, Rebecca S.; Sivaraman, Komagal Kannan; Paiardini, Alessandro; McGowan, Sheena

doi:10.1002/prot.24771

Cited by 12 publications

(13 citation statements)

References 20 publications

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“…Pf A-M1 and Pf A-M17 are essential for parasite survival and are validated antimalarial drug targets [ 7 – 10 ]. To date, different inhibitor scaffolds have been described as competitive dual inhibitors of Pf A-M1 and Pf A-M17, including peptide-based bestatin analogues, phosphinopeptides and phosphonic acids [ 7 – 9 , 11 – 14 ]. Recently, our group has also identified hydroxamic acid containing compounds as potent inhibitors of Pf A-M1 and Pf A-M17 that show anti-parasitic activity in the nanomolar range [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Purity (90% or higher) of these compounds was confirmed by vendors. Aminopeptidase activity and K i values for both enzymes were determined as already described [ 14 , 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…The two aminopeptidases are each encoded by non-homologous genes and have been validated in vitro and in vivo as drug targets, as inhibition of their activity can control both murine and laboratory malaria parasites [ 10 ]. Previous work within our group has identified potent dual inhibitors of the enzymes [ 7 , 9 , 11 – 14 ], which bind via coordination of the zinc ions by a zinc binding group (ZBG).…”

Section: Introductionmentioning

confidence: 99%

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Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening

et al. 2015

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The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual ‘hits’. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range) against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.

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Section: Discussionmentioning

confidence: 99%

“…Purity (90% or higher) of these compounds was confirmed by vendors. Aminopeptidase activity and K i values for both enzymes were determined as already described [ 14 , 15 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening

et al. 2015

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“…This common substrate specificity, together with a very conserved structure and catalytic mechanism, makes the development of highly selective inhibitors of a given metallo-aminopeptidase obviously challenging [ 11 , 28 , 29 , 30 , 31 ]. Thereby the most notable inhibitors, depicted in Figure 1 , consist in tetrahedral intermediate mimics, as for the widely used bestatin [ 32 ] and phosphinic [ 33 ]/phosphonic [ 34 ] acid derivatives, or zinc-chelating group inserted in a peptide-like scaffold, as for hydroxamic acids [ 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases

et al. 2018

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The synthesis of racemic substituted 7-amino-5,7,8,9-tetrahydrobenzocyclohepten-6-one hydrochlorides was optimized to enhance reproducibility and increase the overall yield. In order to investigate their specificity, series of enzyme inhibition assays were carried out against a diversity of proteases, covering representative members of aspartic, cysteine, metallo and serine endopeptidases and including eight members of the monometallic M1 family of aminopeptidases as well as two members of the bimetallic M17 and M28 aminopeptidase families. This aminobenzosuberone scaffold indeed demonstrated selective inhibition of M1 aminopeptidases to the exclusion of other tested protease families; it was particularly potent against mammalian APN and its bacterial/parasitic orthologues EcPepN and PfAM1.

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“…Consequently, PfA-M17 is an exciting target for the development of novel antimalarials (19)(20)(21)(22)(23)(24). The crystal structure of PfA-M17 shows the homohexameric arrangement characteristic of M17 aminopeptidase enzymes ( Fig.…”

Section: Introductionmentioning

confidence: 99%

A metal-dependent switch moderates activity of the hexameric M17 aminopeptidases

Drinkwater

Yang

Riley

et al. 2018

Preprint

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18M17 aminopeptidases possess a conserved hexameric arrangement throughout all kingdoms 19 of life. Of particular interest is the M17 from Plasmodium falciparum (PfA-M17), which is a 20 validated antimalarial drug target. Herein we have examined PfA-M17 using an integrated 21 structural biology and biochemical approach to provide the first description of the fundamental role 22 of oligomerisation. We found that, rather than operating as discrete units, the active sites of the 23PfA-M17 hexamer are linked by a dynamic loop, which operates cooperatively to regulate activity. 24Further, we characterised motions in key surface loops that moderate access to the central catalytic 25cavity. Based on our new understanding of the dynamics inherent to PfA-M17, we propose a novel 26 mechanism that would allow exquisite control of enzyme function in response to cellular signals, 27and go on to discuss how, through divergent evolution, this mechanism might have developed to 28 moderate key differences in M17 function across species. 29 30 Introduction: 31

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X‐ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti‐malarial drug targets PfA‐M1 and PfA‐M17

Cited by 12 publications

References 20 publications

Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening

Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening

Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases

A metal-dependent switch moderates activity of the hexameric M17 aminopeptidases

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