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Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway

Rebecca C.S. Edgar, Ghizal Siddiqui, Kathryn Hjerrild, Tess R. Malcolm, Natalie B. Vinh, Chaille T. Webb, Christopher A. MacRaild, Natalie A. Counihan, Darren J. Creek, Peter J Scammells, View ORCID ProfileSheena McGowan, View ORCID ProfileTania F. de Koning-Ward
doi: https://doi.org/10.1101/2021.11.23.469631
Rebecca C.S. Edgar
1School of Medicine, Deakin University, Geelong, 3216, Australia
2The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, 3216, Australia
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Ghizal Siddiqui
5Centre to Impact AMR, Monash University, Melbourne, 3800, Australia
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Kathryn Hjerrild
1School of Medicine, Deakin University, Geelong, 3216, Australia
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Tess R. Malcolm
3Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, 3052, Australia
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Natalie B. Vinh
4Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University Parkville, 3052, Australia
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Chaille T. Webb
3Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, 3052, Australia
5Centre to Impact AMR, Monash University, Melbourne, 3800, Australia
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Christopher A. MacRaild
6Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Australia
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Natalie A. Counihan
1School of Medicine, Deakin University, Geelong, 3216, Australia
2The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, 3216, Australia
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Darren J. Creek
6Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Australia
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Peter J Scammells
4Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University Parkville, 3052, Australia
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Sheena McGowan
3Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, 3052, Australia
5Centre to Impact AMR, Monash University, Melbourne, 3800, Australia
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  • ORCID record for Sheena McGowan
Tania F. de Koning-Ward
1School of Medicine, Deakin University, Geelong, 3216, Australia
2The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, 3216, Australia
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  • ORCID record for Tania F. de Koning-Ward
  • For correspondence: taniad@deakin.edu.au
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Abstract

Plasmodium falciparum, a causative agent of malaria, continues to remain a global health threat since these parasites have developed increasing resistance to all anti-malaria drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. P. falciparum parasites infect human red blood cells where they digest the hosts main protein constituent, hemoglobin. Leucine aminopeptidase PfA-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here we utilize both reverse genetics and a compound specifically designed to inhibit the activity of PfA-M17 to show that PfA-M17 is essential for P. falciparum survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that our inhibitor is on-target for PfA-M17 and has the ability to kill parasites at nanomolar concentrations. Thus, in contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate PfA-M17 as a potential novel drug target.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 23, 2021.
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Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway
Rebecca C.S. Edgar, Ghizal Siddiqui, Kathryn Hjerrild, Tess R. Malcolm, Natalie B. Vinh, Chaille T. Webb, Christopher A. MacRaild, Natalie A. Counihan, Darren J. Creek, Peter J Scammells, Sheena McGowan, Tania F. de Koning-Ward
bioRxiv 2021.11.23.469631; doi: https://doi.org/10.1101/2021.11.23.469631
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Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway
Rebecca C.S. Edgar, Ghizal Siddiqui, Kathryn Hjerrild, Tess R. Malcolm, Natalie B. Vinh, Chaille T. Webb, Christopher A. MacRaild, Natalie A. Counihan, Darren J. Creek, Peter J Scammells, Sheena McGowan, Tania F. de Koning-Ward
bioRxiv 2021.11.23.469631; doi: https://doi.org/10.1101/2021.11.23.469631

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