Inhibition of Plasmodium sporogonic stages by ivermectin and other avermectins

© The Author(s) 2019. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: The transmissible forms of Plasmodium parasites result from a process of sporogony that takes place inside their obligatory mosquito vector and culminates in the formation of mammalian-infective parasite forms. Ivermectin is a member of the avermectin family of endectocides, which has been proposed to inhibit malaria transmission due its insecticidal effect. However, it remains unclear whether ivermectin also exerts a direct action on the parasite's blood and transmission stages. Methods: We employed a rodent model of infection to assess the impact of ivermectin treatment on P. berghei asexual and sexual blood forms in vivo. We then made use of a newly established luminescence-based methodology to evaluate the activity of ivermectin and other avermectins against the sporogonic stages of P. berghei parasites in vitro independent of their role on mosquito physiology. Results: Our results show that whereas ivermectin does not affect the parasite's parasitemia, gametocytemia or exflagellation in the mammalian host, several members of the avermectin family of compounds exert a strong inhibitory effect on the generation and development of P. berghei oocysts. Conclusions: Our results shed light on the action of avermectins against Plasmodium transmission stages and highlight the potential of these compounds to help prevent the spread of malaria.This work was carried out with the support of grants PTDC-BBB-BMD-2695-2014 and 02/SAICT/2017/29550 from Fundação para a Ciência e Tecnologia, Portugal (FCT) to AMM and MP, respectively, and by FCT grant UID/BIM/50005/2019 (Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado). RA was supported by FCT’s fellowship BD/131334/2017, AMM was supported by FCT’s fellowship SFRH/BPD/80693/2011, and MP was supported by FCT’s Investigador FCT 2013 and CEEC 2018 fellowships.info:eu-repo/semantics/publishedVersio

The impact of antiretroviral therapy on malaria parasite transmission

Copyright © 2020 Azevedo, Mendes and Prudêncio. 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.Coendemicity between the human immunodeficiency virus (HIV) and Plasmodium parasites, the causative agents of acquired immunodeficiency syndrome (AIDS) and malaria, respectively, occurs in several regions around the world. Although the impact of the interaction between these two organisms is not well understood, it is thought that the outcome of either disease may be negatively influenced by coinfection. Therefore, it is important to understand how current first-line antiretroviral therapies (ART) might impact Plasmodium infection in these regions. Here, we describe the effect of 18 antiretroviral compounds and of first-line ART on the blood and sporogonic stages of Plasmodium berghei in vitro and in vivo. We show that the combination zidovudine + lamivudine + lopinavir/ritonavir (LPV/r), employed as first-line HIV treatment in the field, has a strong inhibitory activity on the sporogonic stages of P. berghei and that several non-nucleoside reverse transcriptase inhibitors (NNRTI) have a moderate effect on this stage of the parasite's life cycle. Our results expose the effect of current first-line ART on Plasmodium infection and identify potential alternative therapies for HIV/AIDS that might impact malaria transmission.info:eu-repo/semantics/publishedVersio

A new strategy against malaria – antimalarial ionic liquids derived from aminoquinolines and fatty acids

Based on the recent promising results obtained by us, where ionic liquids (ILs) derived from primaquine were found as triple-stage antimalarial hits, we have now produced, by simple, quantitative, and low-cost methods, new ILs via simple acid-base titration of antimalarial aminoquinolines (primaquine and chloroquine) with natural fatty acids (Figure 1). We have also synthesized, in good to high yields, the covalent amide analogues of these ILs (Figure 1), in order to establish how the nature of the chemical bond (ionic ammonium carboxylate versus covalent amide) between both building blocks influences the physico-chemical and biological properties of the final compounds. Results obtained thus far allow us to conclude that both ionic and covalent compounds (i) have higher thermostability than the parent drugs, and (ii) display remarkable in vitro activity against liver-stage malaria parasites.info:eu-repo/semantics/publishedVersio

Transient complexes of redox proteins: structural and dynamic details from NMR studies

Redox proteins participate in many metabolic routes, in particular those related to energy conversion. Protein-protein complexes of redox proteins are characterized by a weak affinity and a short lifetime. Twodimensional NMR spectroscopy has been applied to many redox protein complexes, providing a wealth of information about the process of complex formation, the nature of the interface and the dynamic properties of the complex. These studies have shown that some complexes are non-specific and exist as a dynamic ensemble of orientations while in other complexes the proteins assume a single orientation. The binding interface in these complexes consists of a small hydrophobic patch for specificity, surrounded by polar, uncharged residues that may enhance dissociation, and, in most complexes, a ring or patch of charged residues that enhances the association by electrostatic interactions. The entry and exit port of the electrons is located within the hydrophobic interaction site, ensuring rapid electron transfer from one redox centre to the next

Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.With its strong effect on vector-borne diseases, and insecticidal effect on mosquito vectors of malaria, inhibition of sporogonic and blood-stage development of Plasmodium falciparum, as well as in vitro and in vivo impairment of the P. berghei development inside hepatocytes, ivermectin (IVM) continues to represent an antimalarial therapeutic worthy of investigation. The in vitro activity of the first-generation IVM hybrids synthesized by appending the IVM macrolide with heterocyclic and organometallic antimalarial pharmacophores, against the blood-stage and liver-stage infections by Plasmodium parasites prompted us to design second-generation molecular hybrids of IVM. Here, a structural modification of IVM to produce novel molecular hybrids by using sub-structures of 4- and 8-aminoquinolines, the time-tested antiplasmodial agents used for treating the blood and hepatic stage of Plasmodium infections, respectively, is presented. Successful isolation of regioisomers and epimers has been demonstrated, and the evaluation of their in vitro antiplasmodial activity against both the blood stages of P. falciparum and the hepatic stages of P. berghei have been undertaken. These compounds displayed structure-dependent antiplasmodial activity, in the nM range, which was more potent than that of IVM, its aglycon or primaquine, highlighting the superiority of this hybridization strategy in designing new antiplasmodial agents.KS thanks SERB, DST for the grant (EMR/2017/000520) and Guru Nanak Dev University, Amritsar for funding under the RUSA-II scheme as well as facilities. MP acknowledges Fundação para a Ciência e Tecnologia, Portugal, for Grant PTDC-SAU-INF-29550/2017. LS is thankful to University Grants Commission (UGC), New Delhi for funding under Rajiv Gandhi National Fellowship.info:eu-repo/semantics/publishedVersio

Estudo comparativo da microinfiltração marginal em molares restaurados com cimentos de ionómero de vidro convencional e reforçado por resina

Dissertação para obtenção do grau de Mestre no Instituto Superior de Ciências da Saúde Egas MonizObjectivo: Avaliar o grau de microinfiltração marginal em molares restaurados com Cimento de Ionómero de Vidro Convencional de Alta Viscosidade e com Cimento de Ionómero de Vidro Reforçado por Resina de diferentes marcas comerciais. Materiais e Métodos: Utilizando os Cimentos de Ionómero de Vidro Convencional de Alta Viscosidade (Ketac Molar e o sistema Equia) e o Cimento de Ionómero de Vidro Reforçado por Resina (Photac Fil) foram realizadas 45 restaurações Classe I em molares hígidos previamente extraídos. Os molares foram imersos durante 24 horas numa solução de azul de metileno a 2%. Posteriormente foram seccionados longitudinalmente no sentido Mesio- Distal. Finalmente foi realizada a leitura de resultados através da observação numa de lupa com um aumento de 40 vezes. Para a análise estatística foi utilizado o teste Chi-quadrado. Resultados: Não existiram diferenças estatisticamente relevantes entre os três materiais utilizados. O material que apresentou maior grau de microinfiltração foi o Ketac Molar e o material que apresentou menor grau de microinfiltração foi o Photac Fil. Conclusão: Todos os materiais apresentaram algum grau de microinfiltração. O Photac Fil foi o material com menor grau de microinfiltração, seguido do Equia e por fim o Ketac Molar

Inhibition of Plasmodium liver infection by Ivermectin

Copyright © 2017 Mendes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.Avermectins are powerful endectocides with an established potential to reduce the incidence of vector-borne diseases. Here, we show that several avermectins inhibit the hepatic stage of Plasmodium infection in vitro Notably, ivermectin potently inhibits liver infection in vivo by impairing parasite development inside hepatocytes. This impairment has a clear impact on the ensuing blood stage parasitemia, reducing disease severity and enhancing host survival. Ivermectin has been proposed as a tool to control malaria transmission because of its effects on the mosquito vector. Our study extends the effect of ivermectin to the early stages of mammalian host infection and supports the inclusion of this multipurpose drug in malaria control strategies.A.M.M., P.M., and M.P. acknowledge the Fundação para a Ciência e Tecnologia, Portugal, for grants SFRH/BPD/80693/2011, SFRH/BD/71098/2010, and Investigador FCT (2013), respectively. This work was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) grant PTDC/SAU-MIC/117060/2010.info:eu-repo/semantics/publishedVersio

Dual-stage triterpenoids from an African medicinal plant targeting the malaria parasite

Sixteen triterpenoids (1–16), previously isolated from the aerial parts of the African medicinal plant Momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of Plasmodium berghei, measuring the luminescence intensity in Huh-7 cells infected with a firefly lucif erase-expressing P. berghei line, PbGFP-Luccon. Toxicity of compounds (1–16) was assessed on the same cell line through the fluorescence measurement of cell confluency. The highest activity was displayed by a derivative bearing two acetyl residues, karavoate B (7), which led to a dose-dependent decrease in the P. berghei infection rate, exhibiting a very significant activity at the lowest concentration employed (1 lM) and no toxicity towards the Huh-7 cells. It is noteworthy that, in previous studies, this compound was found to be a strong inhibitor of blood-stages of Plasmodium falciparum, thus displaying a dual-stage antimalarial activity.info:eu-repo/semantics/publishedVersio

A crucial role for the C‐terminal domain of exported protein 1 during the mosquito and hepatic stages of the Plasmodium bergheilife cycle

© 2019 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Intracellular Plasmodium parasites develop inside a parasitophorous vacuole (PV), a specialised compartment enclosed by a membrane (PVM) that contains proteins of both host and parasite origin. Although exported protein 1 (EXP1) is one of the earliest described parasitic PVM proteins, its function throughout the Plasmodium life cycle remains insufficiently understood. Here, we show that whereas the N-terminus of Plasmodium berghei EXP1 (PbEXP1) is essential for parasite survival in the blood, parasites lacking PbEXP1's entire C-terminal (CT) domain replicate normally in the blood but cause less severe pathology than their wild-type counterparts. Moreover, truncation of PbEXP1's CT domain not only impairs parasite development in the mosquito but also abrogates PbEXP1 localization to the PVM of intrahepatic parasites, severely limiting their replication and preventing their egress into the blood. Our findings highlight the importance of EXP1 during the Plasmodium life cycle and identify this protein as a promising target for antiplasmodial intervention.This study was sup- ported by German Research Foundation (Deutsche Forschungsgemeinschaft ‐ DFG) Grants SPP 1580 (to A.‐K. M.) and SFB1129 (to A.‐K. M.); Fundação para a Ciência e Tecnologia, Portugal (FCT‐PT) Grants UID/BIM/50005/2019 (Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado) and 02/SAICT/2017 (to M. P.). M. S.‐V. was supported by an FCT‐PT Grant PD/BD/105838/2014. D. F. was supported by FEEI and FCT‐MEC. M. P. was supported by FCT‐PT Investigador FCT 2013 and CEEC 2018 fellowship. A.‐K. M. was a recipient of a Maternity Leave Stipend by the German Center for Infection Research (DZIF, Heidelberg Site)info:eu-repo/semantics/publishedVersio