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

Nyssa Drinkwater, Rebecca S Bamert, Komagal Kannan Sivaraman, Alessandro Paiardini, Sheena McGowan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

New antimalarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases PfA-M1 and PfA-M17 is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)789 - 795
Number of pages7
JournalProteins: Structure, Function, and Bioinformatics
Volume83
Issue number4
DOIs
Publication statusPublished - 2015

Cite this

Drinkwater, Nyssa ; Bamert, Rebecca S ; Kannan Sivaraman, Komagal ; Paiardini, Alessandro ; McGowan, Sheena. / X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17. In: Proteins: Structure, Function, and Bioinformatics. 2015 ; Vol. 83, No. 4. pp. 789 - 795.
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abstract = "New antimalarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases PfA-M1 and PfA-M17 is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17. This article is protected by copyright. All rights reserved.",
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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. / Drinkwater, Nyssa; Bamert, Rebecca S; Kannan Sivaraman, Komagal; Paiardini, Alessandro; McGowan, Sheena.

In: Proteins: Structure, Function, and Bioinformatics, Vol. 83, No. 4, 2015, p. 789 - 795.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - X-ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti-malarial drug targets PfA-M1 and PfA-M17

AU - Drinkwater, Nyssa

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AU - Kannan Sivaraman, Komagal

AU - Paiardini, Alessandro

AU - McGowan, Sheena

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AB - New antimalarial treatments are desperately required to face the spread of drug resistant parasites. Inhibition of metalloaminopeptidases PfA-M1 and PfA-M17 is a validated therapeutic strategy for treatment of Plasmodium falciparum malaria. Here we describe the crystal structures of PfA-M1 and PfA-M17 bound to chemotherapeutic agent Tosedostat. The inhibitor occupies the enzymes putative product egress channels in addition to the substrate binding pockets; however, adopts different binding poses when bound to PfA-M1 and PfA-M17. These findings will be valuable for the continued development of selective inhibitors of PfA-M1 and PfA-M17. This article is protected by copyright. All rights reserved.

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