Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases

Natalie B. Vinh, Nyssa Drinkwater, Tess R. Malcolm, Michael Kassiou, Leonardo Lucantoni, Peter M. Grin, Georgina S. Butler, Sandra Duffy, Christopher M. Overall, Vicky M. Avery, Peter J. Scammells, Sheena McGowan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum (Pf-M1 and Pf-M17) and P. vivax (Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1′ pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.

Original languageEnglish
Pages (from-to)622-640
Number of pages19
JournalJournal of Medicinal Chemistry
Volume62
Issue number2
DOIs
Publication statusPublished - 24 Jan 2019

Cite this

Vinh, Natalie B. ; Drinkwater, Nyssa ; Malcolm, Tess R. ; Kassiou, Michael ; Lucantoni, Leonardo ; Grin, Peter M. ; Butler, Georgina S. ; Duffy, Sandra ; Overall, Christopher M. ; Avery, Vicky M. ; Scammells, Peter J. ; McGowan, Sheena. / Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 2. pp. 622-640.
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abstract = "There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum (Pf-M1 and Pf-M17) and P. vivax (Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1′ pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.",
author = "Vinh, {Natalie B.} and Nyssa Drinkwater and Malcolm, {Tess R.} and Michael Kassiou and Leonardo Lucantoni and Grin, {Peter M.} and Butler, {Georgina S.} and Sandra Duffy and Overall, {Christopher M.} and Avery, {Vicky M.} and Scammells, {Peter J.} and Sheena McGowan",
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doi = "10.1021/acs.jmedchem.8b01310",
language = "English",
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Vinh, NB, Drinkwater, N, Malcolm, TR, Kassiou, M, Lucantoni, L, Grin, PM, Butler, GS, Duffy, S, Overall, CM, Avery, VM, Scammells, PJ & McGowan, S 2019, 'Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases' Journal of Medicinal Chemistry, vol. 62, no. 2, pp. 622-640. https://doi.org/10.1021/acs.jmedchem.8b01310

Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases. / Vinh, Natalie B.; Drinkwater, Nyssa; Malcolm, Tess R.; Kassiou, Michael; Lucantoni, Leonardo; Grin, Peter M.; Butler, Georgina S.; Duffy, Sandra; Overall, Christopher M.; Avery, Vicky M.; Scammells, Peter J.; McGowan, Sheena.

In: Journal of Medicinal Chemistry, Vol. 62, No. 2, 24.01.2019, p. 622-640.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Vinh, Natalie B.

AU - Drinkwater, Nyssa

AU - Malcolm, Tess R.

AU - Kassiou, Michael

AU - Lucantoni, Leonardo

AU - Grin, Peter M.

AU - Butler, Georgina S.

AU - Duffy, Sandra

AU - Overall, Christopher M.

AU - Avery, Vicky M.

AU - Scammells, Peter J.

AU - McGowan, Sheena

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AB - There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum (Pf-M1 and Pf-M17) and P. vivax (Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1′ pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.

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