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

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.
Original languageEnglish
Pages (from-to)43-64
Number of pages22
JournalEuropean Journal of Medicinal Chemistry
Volume110
DOIs
Publication statusPublished - 3 Mar 2016

Keywords

  • plasmodium falciparum
  • malaria
  • aminopeptidase inhibitors
  • hydroxamic acid
  • zinc-binding group

Cite this

Drinkwater, Nyssa ; Vinh, Natalie B. ; Mistry, Shailesh N. ; Bamert, Rebecca S. ; Ruggeri, Chiara ; Holleran, John P. ; Loganathan, Sasdekumar ; Paiardini, Alessandro ; Charman, Susan A. ; Powell, Andrew K. ; Avery, Vicky M. ; McGowan, Sheena ; Scammells, Peter J. / Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 110. pp. 43-64.
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abstract = "Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.",
keywords = "plasmodium falciparum, malaria, aminopeptidase inhibitors, hydroxamic acid, zinc-binding group",
author = "Nyssa Drinkwater and Vinh, {Natalie B.} and Mistry, {Shailesh N.} and Bamert, {Rebecca S.} and Chiara Ruggeri and Holleran, {John P.} and Sasdekumar Loganathan and Alessandro Paiardini and Charman, {Susan A.} and Powell, {Andrew K.} and Avery, {Vicky M.} and Sheena McGowan and Scammells, {Peter J.}",
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Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. / Drinkwater, Nyssa; Vinh, Natalie B.; Mistry, Shailesh N.; Bamert, Rebecca S.; Ruggeri, Chiara; Holleran, John P.; Loganathan, Sasdekumar; Paiardini, Alessandro; Charman, Susan A.; Powell, Andrew K.; Avery, Vicky M.; McGowan, Sheena; Scammells, Peter J.

In: European Journal of Medicinal Chemistry, Vol. 110, 03.03.2016, p. 43-64.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Drinkwater, Nyssa

AU - Vinh, Natalie B.

AU - Mistry, Shailesh N.

AU - Bamert, Rebecca S.

AU - Ruggeri, Chiara

AU - Holleran, John P.

AU - Loganathan, Sasdekumar

AU - Paiardini, Alessandro

AU - Charman, Susan A.

AU - Powell, Andrew K.

AU - Avery, Vicky M.

AU - McGowan, Sheena

AU - Scammells, Peter J.

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AB - Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.

KW - plasmodium falciparum

KW - malaria

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KW - hydroxamic acid

KW - zinc-binding group

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