Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex
In the fight against malaria, the key is early treatment with antimalarial chemotherapy, such as artemisinin-based combination treatments (ACTs). However, Plasmodium has acquired multidrug resistance, including the emergence of P. falciparum strains with resistance to ACT. The development of novel a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2022.1047269/full |
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| author | Camila Martins Gomes Morais Camila Martins Gomes Morais Ramayana Morais de Medeiros Brito Ramayana Morais de Medeiros Brito Aleksandra Weselucha-Birczyńska Valeska Santana de Sena Pereira Valeska Santana de Sena Pereira Jordam William Pereira-Silva Jordam William Pereira-Silva Alexandre Menezes Felipe Arley Costa Pessoa Martyna Kucharska Malwina Birczyńska-Zych Malwina Birczyńska-Zych Claudia María Ríos-Velásquez Valter Ferreira de Andrade-Neto |
| author_facet | Camila Martins Gomes Morais Camila Martins Gomes Morais Ramayana Morais de Medeiros Brito Ramayana Morais de Medeiros Brito Aleksandra Weselucha-Birczyńska Valeska Santana de Sena Pereira Valeska Santana de Sena Pereira Jordam William Pereira-Silva Jordam William Pereira-Silva Alexandre Menezes Felipe Arley Costa Pessoa Martyna Kucharska Malwina Birczyńska-Zych Malwina Birczyńska-Zych Claudia María Ríos-Velásquez Valter Ferreira de Andrade-Neto |
| author_sort | Camila Martins Gomes Morais |
| collection | DOAJ |
| description | In the fight against malaria, the key is early treatment with antimalarial chemotherapy, such as artemisinin-based combination treatments (ACTs). However, Plasmodium has acquired multidrug resistance, including the emergence of P. falciparum strains with resistance to ACT. The development of novel antimalarial molecules, that are capable of interfering in the asexual and sexual blood stages, is important to slow down the transmission in endemic areas. In this work, we studied the ability of the mettalo copper-cinchonine complex to interfere in the sexual and asexual stages of Plasmodium. The tested compound in the in vitro assay was a cinchonine derivative, named CinCu (Bis[Cinchoninium Tetrachlorocuprate(II)]trihydrate). Its biological functions were assessed by antiplasmodial activity in vitro against chloroquine-resistant P. falciparum W2 strain. The mice model of P. berghei ANKA infection was used to analyze the antimalarial activity of CinCu and chloroquine and their acute toxicity. The oocyst formation-blocking assay was performed by experimental infection of Anopheles aquasalis with P. vivax infected blood, which was treated with different concentrations of CinCu, cinchonine, and primaquine. We found that CinCu was able to suppress as high as 81.58% of parasitemia in vitro, being considered a molecule with high antiplasmodial activity and low toxicity. The in vivo analysis showed that CinCu suppressed parasitemia at 34% up to 87.19%, being a partially active molecule against the blood-stage forms of P. berghei ANKA, without inducing severe clinical signs in the treated groups. The transmission-blocking assay revealed that both cinchonine and primaquine were able to reduce the infection intensity of P. vivax in A. aquasalis, leading to a decrease in the number of oocysts recovered from the mosquitoes’ midgut. Regarding the effect of CinCu, the copper-complex was not able to induce inhibition of P. vivax infection; however, it was able to induce an important reduction in the intensity of oocyst formation by about 2.4 times. It is plausible that the metallo-compound also be able to interfere with the differentiation of parasite stages and/or ookinete-secreted chitinase into the peritrophic matrix of mosquitoes, promoting a reduction in the number of oocysts formed. Taken together, the results suggest that this compound is promising as a prototype for the development of new antimalarial drugs. Furthermore, our study can draw a new pathway for repositioning already-known antimalarial drugs by editing their chemical structure to improve the antimalarial activity against the asexual and sexual stages of the parasite. |
| first_indexed | 2024-04-11T15:18:00Z |
| format | Article |
| id | doaj.art-359a2dcb89994e6093216f0aed5cad7e |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-04-11T15:18:00Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-359a2dcb89994e6093216f0aed5cad7e2022-12-22T04:16:26ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-12-011210.3389/fcimb.2022.10472691047269Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complexCamila Martins Gomes Morais0Camila Martins Gomes Morais1Ramayana Morais de Medeiros Brito2Ramayana Morais de Medeiros Brito3Aleksandra Weselucha-Birczyńska4Valeska Santana de Sena Pereira5Valeska Santana de Sena Pereira6Jordam William Pereira-Silva7Jordam William Pereira-Silva8Alexandre Menezes9Felipe Arley Costa Pessoa10Martyna Kucharska11Malwina Birczyńska-Zych12Malwina Birczyńska-Zych13Claudia María Ríos-Velásquez14Valter Ferreira de Andrade-Neto15Laboratory of Malaria and Toxoplasmosis Biology, Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, BrazilPost-Graduate Program in Parasitic Biology, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, BrazilLaboratory of Malaria and Toxoplasmosis Biology, Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, BrazilLaboratory of Immunology and Genomics of Parasites, Department of Parasitology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, BrazilDepartment of Chemical Physics, Faculty of Chemistry, Jagiellonian University, Kraków, PolandLaboratory of Malaria and Toxoplasmosis Biology, Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, BrazilPost-Graduate Program in Biochemistry and Molecular Biology, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, BrazilLaboratory of Infectious Disease Ecology in the Amazon, Leônidas and Maria Deane Institute, Fiocruz, Manaus, AM, BrazilPost-Graduate Program in Living Conditions and Health Situations in the Amazon, Leônidas and Maria Deane Institute, Fiocruz, Manaus, AM, BrazilPost-Graduate Program in Biology of Host-Pathogen interaction, Leônidas and Maria Deane Institute, Fiocruz, Manaus, AM, BrazilLaboratory of Infectious Disease Ecology in the Amazon, Leônidas and Maria Deane Institute, Fiocruz, Manaus, AM, BrazilDepartment of Chemical Physics, Faculty of Chemistry, Jagiellonian University, Kraków, PolandDepartment of Infectious and Tropical Diseases, Medical College, Jagiellonian University, Kraków, Poland0Department of Infectious Diseases, The University Hospital in Kraków, Kraków, PolandLaboratory of Infectious Disease Ecology in the Amazon, Leônidas and Maria Deane Institute, Fiocruz, Manaus, AM, BrazilLaboratory of Malaria and Toxoplasmosis Biology, Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal, RN, BrazilIn the fight against malaria, the key is early treatment with antimalarial chemotherapy, such as artemisinin-based combination treatments (ACTs). However, Plasmodium has acquired multidrug resistance, including the emergence of P. falciparum strains with resistance to ACT. The development of novel antimalarial molecules, that are capable of interfering in the asexual and sexual blood stages, is important to slow down the transmission in endemic areas. In this work, we studied the ability of the mettalo copper-cinchonine complex to interfere in the sexual and asexual stages of Plasmodium. The tested compound in the in vitro assay was a cinchonine derivative, named CinCu (Bis[Cinchoninium Tetrachlorocuprate(II)]trihydrate). Its biological functions were assessed by antiplasmodial activity in vitro against chloroquine-resistant P. falciparum W2 strain. The mice model of P. berghei ANKA infection was used to analyze the antimalarial activity of CinCu and chloroquine and their acute toxicity. The oocyst formation-blocking assay was performed by experimental infection of Anopheles aquasalis with P. vivax infected blood, which was treated with different concentrations of CinCu, cinchonine, and primaquine. We found that CinCu was able to suppress as high as 81.58% of parasitemia in vitro, being considered a molecule with high antiplasmodial activity and low toxicity. The in vivo analysis showed that CinCu suppressed parasitemia at 34% up to 87.19%, being a partially active molecule against the blood-stage forms of P. berghei ANKA, without inducing severe clinical signs in the treated groups. The transmission-blocking assay revealed that both cinchonine and primaquine were able to reduce the infection intensity of P. vivax in A. aquasalis, leading to a decrease in the number of oocysts recovered from the mosquitoes’ midgut. Regarding the effect of CinCu, the copper-complex was not able to induce inhibition of P. vivax infection; however, it was able to induce an important reduction in the intensity of oocyst formation by about 2.4 times. It is plausible that the metallo-compound also be able to interfere with the differentiation of parasite stages and/or ookinete-secreted chitinase into the peritrophic matrix of mosquitoes, promoting a reduction in the number of oocysts formed. Taken together, the results suggest that this compound is promising as a prototype for the development of new antimalarial drugs. Furthermore, our study can draw a new pathway for repositioning already-known antimalarial drugs by editing their chemical structure to improve the antimalarial activity against the asexual and sexual stages of the parasite.https://www.frontiersin.org/articles/10.3389/fcimb.2022.1047269/fullPlasmodiummalaria treatmentcinchoninemettalo copper complexesantimalarial drugs |
| spellingShingle | Camila Martins Gomes Morais Camila Martins Gomes Morais Ramayana Morais de Medeiros Brito Ramayana Morais de Medeiros Brito Aleksandra Weselucha-Birczyńska Valeska Santana de Sena Pereira Valeska Santana de Sena Pereira Jordam William Pereira-Silva Jordam William Pereira-Silva Alexandre Menezes Felipe Arley Costa Pessoa Martyna Kucharska Malwina Birczyńska-Zych Malwina Birczyńska-Zych Claudia María Ríos-Velásquez Valter Ferreira de Andrade-Neto Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex Frontiers in Cellular and Infection Microbiology Plasmodium malaria treatment cinchonine mettalo copper complexes antimalarial drugs |
| title | Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex |
| title_full | Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex |
| title_fullStr | Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex |
| title_full_unstemmed | Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex |
| title_short | Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex |
| title_sort | blood stage antiplasmodial activity and oocyst formation blockage of metallo copper cinchonine complex |
| topic | Plasmodium malaria treatment cinchonine mettalo copper complexes antimalarial drugs |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2022.1047269/full |
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