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Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite

Cysteine proteases of malaria parasites have been recognized as potential targets in antimalarial drug development as they play pivotal roles in the biology of these parasites. However, strict regulation of their activities is also necessary to minimize or prevent deleterious damage to the parasite...

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Autores principales: Lê, Hương Giang, Kang, Jung-Mi, Võ, Tuấn Cường, Nguyễn, Thảo Dương, Jung, Myunghwan, Shin, Min Kyoung, Yoo, Won Gi, Na, Byoung-Kuk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142985/
https://www.ncbi.nlm.nih.gov/pubmed/35631126
http://dx.doi.org/10.3390/pathogens11050605
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author Lê, Hương Giang
Kang, Jung-Mi
Võ, Tuấn Cường
Nguyễn, Thảo Dương
Jung, Myunghwan
Shin, Min Kyoung
Yoo, Won Gi
Na, Byoung-Kuk
author_facet Lê, Hương Giang
Kang, Jung-Mi
Võ, Tuấn Cường
Nguyễn, Thảo Dương
Jung, Myunghwan
Shin, Min Kyoung
Yoo, Won Gi
Na, Byoung-Kuk
author_sort Lê, Hương Giang
collection PubMed
description Cysteine proteases of malaria parasites have been recognized as potential targets in antimalarial drug development as they play pivotal roles in the biology of these parasites. However, strict regulation of their activities is also necessary to minimize or prevent deleterious damage to the parasite and the host. Previously, we have characterized falcipain family cysteine proteases of Plasmodium malariae, named as malapains (MPs). MPs are active hemoglobinases. They also may participate in the release of merozoites from mature schizonts by facilitating remodeling of erythrocyte skeleton proteins. In this study, we identified and characterized an endogenous inhibitor of cysteine protease of P. malariae (PmICP). PmICP shared similar structural and biochemical properties with ICPs from other Plasmodium species. Recombinant PmICP showed a broad range of inhibitory activities against diverse cysteine proteases such as falcipain family enzymes (MP-2, MP-4, VX-3, VX-4, and FP-3), papain, and human cathepsins B and L, with stronger inhibitory activities against falcipain family enzymes. The inhibitory activity of PmICP was not affected by pH. PmICP was thermo-labile, resulting in rapid loss of its inhibitory activity at a high temperature. PmICP effectively inhibited hemoglobin hydrolysis by MPs and regulated maturation of MPs, suggesting its role as a functional regulator of MPs.
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spelling pubmed-91429852022-05-29 Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite Lê, Hương Giang Kang, Jung-Mi Võ, Tuấn Cường Nguyễn, Thảo Dương Jung, Myunghwan Shin, Min Kyoung Yoo, Won Gi Na, Byoung-Kuk Pathogens Article Cysteine proteases of malaria parasites have been recognized as potential targets in antimalarial drug development as they play pivotal roles in the biology of these parasites. However, strict regulation of their activities is also necessary to minimize or prevent deleterious damage to the parasite and the host. Previously, we have characterized falcipain family cysteine proteases of Plasmodium malariae, named as malapains (MPs). MPs are active hemoglobinases. They also may participate in the release of merozoites from mature schizonts by facilitating remodeling of erythrocyte skeleton proteins. In this study, we identified and characterized an endogenous inhibitor of cysteine protease of P. malariae (PmICP). PmICP shared similar structural and biochemical properties with ICPs from other Plasmodium species. Recombinant PmICP showed a broad range of inhibitory activities against diverse cysteine proteases such as falcipain family enzymes (MP-2, MP-4, VX-3, VX-4, and FP-3), papain, and human cathepsins B and L, with stronger inhibitory activities against falcipain family enzymes. The inhibitory activity of PmICP was not affected by pH. PmICP was thermo-labile, resulting in rapid loss of its inhibitory activity at a high temperature. PmICP effectively inhibited hemoglobin hydrolysis by MPs and regulated maturation of MPs, suggesting its role as a functional regulator of MPs. MDPI 2022-05-22 /pmc/articles/PMC9142985/ /pubmed/35631126 http://dx.doi.org/10.3390/pathogens11050605 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lê, Hương Giang
Kang, Jung-Mi
Võ, Tuấn Cường
Nguyễn, Thảo Dương
Jung, Myunghwan
Shin, Min Kyoung
Yoo, Won Gi
Na, Byoung-Kuk
Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite
title Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite
title_full Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite
title_fullStr Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite
title_full_unstemmed Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite
title_short Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite
title_sort inhibitor of cysteine protease of plasmodium malariae regulates malapains, endogenous cysteine proteases of the parasite
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142985/
https://www.ncbi.nlm.nih.gov/pubmed/35631126
http://dx.doi.org/10.3390/pathogens11050605
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