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Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase

Malaria remains one of the most prominent and dangerous tropical diseases. While artemisinin and analogs have been used as first-line drugs for the past decades, due to the high mutational rate and rapid adaptation to the environment of the parasite, it remains urgent to develop new antimalarials. T...

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Autores principales: Wang, Chao, Krüger, Arne, Du, Xiaochen, Wrenger, Carsten, Groves, Matthew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931299/
https://www.ncbi.nlm.nih.gov/pubmed/35310840
http://dx.doi.org/10.3389/fcimb.2022.841833
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author Wang, Chao
Krüger, Arne
Du, Xiaochen
Wrenger, Carsten
Groves, Matthew R.
author_facet Wang, Chao
Krüger, Arne
Du, Xiaochen
Wrenger, Carsten
Groves, Matthew R.
author_sort Wang, Chao
collection PubMed
description Malaria remains one of the most prominent and dangerous tropical diseases. While artemisinin and analogs have been used as first-line drugs for the past decades, due to the high mutational rate and rapid adaptation to the environment of the parasite, it remains urgent to develop new antimalarials. The pyrimidine biosynthesis pathway plays an important role in cell growth and proliferation. Unlike human host cells, the malarial parasite lacks a functional pyrimidine salvage pathway, meaning that RNA and DNA synthesis is highly dependent on the de novo synthesis pathway. Thus, direct or indirect blockage of the pyrimidine biosynthesis pathway can be lethal to the parasite. Aspartate transcarbamoylase (ATCase), catalyzes the second step of the pyrimidine biosynthesis pathway, the condensation of L-aspartate and carbamoyl phosphate to form N-carbamoyl aspartate and inorganic phosphate, and has been demonstrated to be a promising target both for anti-malaria and anti-cancer drug development. This is highlighted by the discovery that at least one of the targets of Torin2 – a potent, yet unselective, antimalarial – is the activity of the parasite transcarbamoylase. Additionally, the recent discovery of an allosteric pocket of the human homology raises the intriguing possibility of species selective ATCase inhibitors. We recently exploited the available crystal structures of the malarial aspartate transcarbamoylase to perform a fragment-based screening to identify hits. In this review, we summarize studies on the structure of Plasmodium falciparum ATCase by focusing on an allosteric pocket that supports the catalytic mechanisms.
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spelling pubmed-89312992022-03-19 Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase Wang, Chao Krüger, Arne Du, Xiaochen Wrenger, Carsten Groves, Matthew R. Front Cell Infect Microbiol Cellular and Infection Microbiology Malaria remains one of the most prominent and dangerous tropical diseases. While artemisinin and analogs have been used as first-line drugs for the past decades, due to the high mutational rate and rapid adaptation to the environment of the parasite, it remains urgent to develop new antimalarials. The pyrimidine biosynthesis pathway plays an important role in cell growth and proliferation. Unlike human host cells, the malarial parasite lacks a functional pyrimidine salvage pathway, meaning that RNA and DNA synthesis is highly dependent on the de novo synthesis pathway. Thus, direct or indirect blockage of the pyrimidine biosynthesis pathway can be lethal to the parasite. Aspartate transcarbamoylase (ATCase), catalyzes the second step of the pyrimidine biosynthesis pathway, the condensation of L-aspartate and carbamoyl phosphate to form N-carbamoyl aspartate and inorganic phosphate, and has been demonstrated to be a promising target both for anti-malaria and anti-cancer drug development. This is highlighted by the discovery that at least one of the targets of Torin2 – a potent, yet unselective, antimalarial – is the activity of the parasite transcarbamoylase. Additionally, the recent discovery of an allosteric pocket of the human homology raises the intriguing possibility of species selective ATCase inhibitors. We recently exploited the available crystal structures of the malarial aspartate transcarbamoylase to perform a fragment-based screening to identify hits. In this review, we summarize studies on the structure of Plasmodium falciparum ATCase by focusing on an allosteric pocket that supports the catalytic mechanisms. Frontiers Media S.A. 2022-03-04 /pmc/articles/PMC8931299/ /pubmed/35310840 http://dx.doi.org/10.3389/fcimb.2022.841833 Text en Copyright © 2022 Wang, Krüger, Du, Wrenger and Groves https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Wang, Chao
Krüger, Arne
Du, Xiaochen
Wrenger, Carsten
Groves, Matthew R.
Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase
title Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase
title_full Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase
title_fullStr Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase
title_full_unstemmed Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase
title_short Novel Highlight in Malarial Drug Discovery: Aspartate Transcarbamoylase
title_sort novel highlight in malarial drug discovery: aspartate transcarbamoylase
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931299/
https://www.ncbi.nlm.nih.gov/pubmed/35310840
http://dx.doi.org/10.3389/fcimb.2022.841833
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