Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates
Abstract Background The unmet demand for effective malaria transmission-blocking agents targeting the transmissible stages of Plasmodium necessitates intensive discovery efforts. In this study, a bioactive bisbenzylisoquinoline (BBIQ), isoliensinine, from Cissampelos pariera (Menispermaceae) rhizome...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Malaria Journal |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12936-023-04590-7 |
| _version_ | 1827943618032173056 |
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| author | Jackson M. Muema James M. Mutunga Meshack A. Obonyo Merid N. Getahun Ramadhan S. Mwakubambanya Hoseah M. Akala Agnes C. Cheruiyot Redemptah A. Yeda Dennis W. Juma Ben Andagalu Jaree L. Johnson Amanda L. Roth Joel L. Bargul |
| author_facet | Jackson M. Muema James M. Mutunga Meshack A. Obonyo Merid N. Getahun Ramadhan S. Mwakubambanya Hoseah M. Akala Agnes C. Cheruiyot Redemptah A. Yeda Dennis W. Juma Ben Andagalu Jaree L. Johnson Amanda L. Roth Joel L. Bargul |
| author_sort | Jackson M. Muema |
| collection | DOAJ |
| description | Abstract Background The unmet demand for effective malaria transmission-blocking agents targeting the transmissible stages of Plasmodium necessitates intensive discovery efforts. In this study, a bioactive bisbenzylisoquinoline (BBIQ), isoliensinine, from Cissampelos pariera (Menispermaceae) rhizomes was identified and characterized for its anti-malarial activity. Methods Malaria SYBR Green I fluorescence assay was performed to evaluate the in vitro antimalarial activity against D6, Dd2, and F32-ART5 clones, and immediate ex vivo (IEV) susceptibility for 10 freshly collected P. falciparum isolates. To determine the speed- and stage-of-action of isoliensinine, an IC50 speed assay and morphological analyses were performed using synchronized Dd2 asexuals. Gametocytocidal activity against two culture-adapted gametocyte-producing clinical isolates was determined using microscopy readouts, with possible molecular targets and their binding affinities deduced in silico. Results Isoliensinine displayed a potent in vitro gametocytocidal activity at mean IC50 gam values ranging between 0.41 and 0.69 µM for Plasmodium falciparum clinical isolates. The BBIQ compound also inhibited asexual replication at mean IC50 Asexual of 2.17 µM, 2.22 µM, and 2.39 µM for D6, Dd2 and F32-ART5 respectively, targeting the late-trophozoite to schizont transition. Further characterization demonstrated a considerable immediate ex vivo potency against human clinical isolates at a geometric mean IC50 IEV = 1.433 µM (95% CI 0.917–2.242). In silico analyses postulated a probable anti-malarial mechanism of action by high binding affinities for four mitotic division protein kinases; Pfnek1, Pfmap2, Pfclk1, and Pfclk4. Additionally, isoliensinine was predicted to possess an optimal pharmacokinetics profile and drug-likeness properties. Conclusion These findings highlight considerable grounds for further exploration of isoliensinine as an amenable scaffold for malaria transmission-blocking chemistry and target validation. |
| first_indexed | 2024-03-13T10:17:34Z |
| format | Article |
| id | doaj.art-be6482cc39094cfb87687c85f9ebef5d |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-03-13T10:17:34Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-be6482cc39094cfb87687c85f9ebef5d2023-05-21T11:09:28ZengBMCMalaria Journal1475-28752023-05-0122111510.1186/s12936-023-04590-7Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolatesJackson M. Muema0James M. Mutunga1Meshack A. Obonyo2Merid N. Getahun3Ramadhan S. Mwakubambanya4Hoseah M. Akala5Agnes C. Cheruiyot6Redemptah A. Yeda7Dennis W. Juma8Ben Andagalu9Jaree L. Johnson10Amanda L. Roth11Joel L. Bargul12Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology (JKUAT)U.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)Department of Biochemistry and Molecular Biology, Egerton UniversityInternational Centre of Insect Physiology and Ecology (Icipe)Department of Biochemistry and Molecular Biology, Egerton UniversityU.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)U.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)U.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)U.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)U.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)U.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)U.S. Army Medical Research Directorate-Africa (USAMRD-A), Centre for Global Health Research (CGHR), Kenya Medical Research Institute (KEMRI)Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology (JKUAT)Abstract Background The unmet demand for effective malaria transmission-blocking agents targeting the transmissible stages of Plasmodium necessitates intensive discovery efforts. In this study, a bioactive bisbenzylisoquinoline (BBIQ), isoliensinine, from Cissampelos pariera (Menispermaceae) rhizomes was identified and characterized for its anti-malarial activity. Methods Malaria SYBR Green I fluorescence assay was performed to evaluate the in vitro antimalarial activity against D6, Dd2, and F32-ART5 clones, and immediate ex vivo (IEV) susceptibility for 10 freshly collected P. falciparum isolates. To determine the speed- and stage-of-action of isoliensinine, an IC50 speed assay and morphological analyses were performed using synchronized Dd2 asexuals. Gametocytocidal activity against two culture-adapted gametocyte-producing clinical isolates was determined using microscopy readouts, with possible molecular targets and their binding affinities deduced in silico. Results Isoliensinine displayed a potent in vitro gametocytocidal activity at mean IC50 gam values ranging between 0.41 and 0.69 µM for Plasmodium falciparum clinical isolates. The BBIQ compound also inhibited asexual replication at mean IC50 Asexual of 2.17 µM, 2.22 µM, and 2.39 µM for D6, Dd2 and F32-ART5 respectively, targeting the late-trophozoite to schizont transition. Further characterization demonstrated a considerable immediate ex vivo potency against human clinical isolates at a geometric mean IC50 IEV = 1.433 µM (95% CI 0.917–2.242). In silico analyses postulated a probable anti-malarial mechanism of action by high binding affinities for four mitotic division protein kinases; Pfnek1, Pfmap2, Pfclk1, and Pfclk4. Additionally, isoliensinine was predicted to possess an optimal pharmacokinetics profile and drug-likeness properties. Conclusion These findings highlight considerable grounds for further exploration of isoliensinine as an amenable scaffold for malaria transmission-blocking chemistry and target validation.https://doi.org/10.1186/s12936-023-04590-7IsoliensinineGametocytesPlasmodium transmission-blockingCissampelos parieraMalaria controlNatural product |
| spellingShingle | Jackson M. Muema James M. Mutunga Meshack A. Obonyo Merid N. Getahun Ramadhan S. Mwakubambanya Hoseah M. Akala Agnes C. Cheruiyot Redemptah A. Yeda Dennis W. Juma Ben Andagalu Jaree L. Johnson Amanda L. Roth Joel L. Bargul Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates Malaria Journal Isoliensinine Gametocytes Plasmodium transmission-blocking Cissampelos pariera Malaria control Natural product |
| title | Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates |
| title_full | Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates |
| title_fullStr | Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates |
| title_full_unstemmed | Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates |
| title_short | Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates |
| title_sort | isoliensinine from cissampelos pariera rhizomes exhibits potential gametocytocidal and anti malarial activities against plasmodium falciparum clinical isolates |
| topic | Isoliensinine Gametocytes Plasmodium transmission-blocking Cissampelos pariera Malaria control Natural product |
| url | https://doi.org/10.1186/s12936-023-04590-7 |
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