Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Drinkwater, N.; Vinh, Nguyen X.; Mistry, Shailesh N.; Bamert, Rebecca S.; Ruggeri, Chiara; Holleran, John; Loganathan, Sasdekumar; Paiardini, Alessandro; Charman, Susan A.; Powell, Andrew K.; Avery, Vicky M.; McGowan, Sheena; Scammells, Peter J.

doi:10.1016/j.ejmech.2016.01.015

Cited by 55 publications

(111 citation statements)

References 42 publications

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“…This observation was further supported by a chemical genetics approach that showed that the absence of M1 aminopeptidase activity resulted in parasite death . Agents that inhibit Pf A‐M1 activity in parasites have been shown to control both laboratory ( P. falciparum ) and murine ( P. c. chabaudi ) models of malaria . Bestatin is an effective inhibitor of Pf A ‐ M1 and derivatives have been developed as chemical probes to investigate the biological role and substrate specificity of the aminopeptidase, although it should be noted that many of these inhibitors are not only selective for Pf A‐M1 but also act on a second, unrelated essential zinc‐dependent aminopeptidase, Pf A‐M17 (clan MF, family M17) .…”

Section: Pathogenic Infectionsmentioning

confidence: 99%

M1 aminopeptidases as drug targets: broad applications or therapeutic niche?

et al. 2017

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M1 aminopeptidase enzymes are a diverse family of metalloenzymes characterized by conserved structure and reaction specificity. Excluding viruses, M1 aminopeptidases are distributed throughout all phyla, and have been implicated in a wide range of functions including cell maintenance, growth and development, and defense. The structure and catalytic mechanism of M1 aminopeptidases are well understood, and make them ideal candidates for the design of small-molecule inhibitors. As a result, many research groups have assessed their utility as therapeutic targets for both infectious and chronic diseases of humans, and many inhibitors with a range of target specificities and potential therapeutic applications have been developed. Herein, we have aimed to address these studies, to determine whether the family of M1 aminopeptidases does in fact present a universal target for the treatment of a diverse range of human diseases. Our analysis indicates that early validation of M1 aminopeptidases as therapeutic targets is often overlooked, which prevents the enzymes from being confirmed as drug targets. This validation cannot be neglected, and needs to include a thorough characterization of enzymes' specific roles within complex physiological pathways. Furthermore, any chemical probes used in target validation must be carefully designed to ensure that specificity over the closely related enzymes has been achieved. While many drug discovery programs that target M1 aminopeptidases remain in their infancy, certain inhibitors have shown promise for the treatment of a range of conditions including malaria, hypertension, and cancer.

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Section: Pathogenic Infectionsmentioning

confidence: 99%

M1 aminopeptidases as drug targets: broad applications or therapeutic niche?

et al. 2017

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“…Analysis of “open” conformation of the M1 aminopeptidases shows that the S1 pocket is poorly organized . An open conformation of Pf A‐M1, nor any bacterial homologs characterized to date, has never been observed experimentally, despite resolution of numerous X‐ray crystal structures . Despite these differences, it appears that changes in the structure, shape, and size of the S1 pocket of these enzymes is still key to their specificity and ultimately, their inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Work from our research group has focused on the design of novel inhibitors of Pf A‐M1 . A previous study modelled a peptide substrate into the active site of Pf A‐M1 using bestatin as a guide .…”

Section: Introductionmentioning

confidence: 99%

Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA‐M1

et al. 2018

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The M1 metallo‐aminopeptidase from Plasmodium falciparum, PfA‐M1, is an attractive drug target for the design of new antimalarials. Bestatin, a broad‐spectrum metalloprotease inhibitor, is a moderate inhibitor of PfA‐M1, and has been used to provide structure–activity relationships to inform drug design. The crystal structure of PfA‐M1 with bestatin bound within its active site has been determined; however, dynamics of the inhibitor and the association or dissociation pathway have yet to be characterized. Here we present an all‐atom molecular dynamics study where we have generated a hidden Markov state model from 2.3 μs of molecular dynamics simulation. Our hidden Markov state model identifies five macrostates that clearly show the events involved in bestatin dissociation from the PfA‐M1 active site. The results show for the first time that bestatin can escape the substrate specificity pockets of the enzyme, primarily due to weak interactions within the pockets. Our approach identifies relevant conformational sampling of the inhibitor inside the enzyme and the protein dynamics that could be exploited to produce potent and selective inhibitors that can differentiate between similar members of the M1 aminopeptidase superfamily.

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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

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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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Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Cited by 55 publications

References 42 publications

M1 aminopeptidases as drug targets: broad applications or therapeutic niche?

M1 aminopeptidases as drug targets: broad applications or therapeutic niche?

Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA‐M1

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

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