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3. Large scale active-learning-guided exploration for in vitro protein production optimization

Author

Olivier Borkowski, Mathilde Koch, Agnès Zettor, Amir Pandi, Angelo Cardoso Batista, Paul Soudier, and Jean-Loup Faulon

Subjects
Science
Abstract

Cell-free lysates are a major platform for in vitro protein production but batch-to-batch variation makes production difficult to predict. Here the authors develop an active learning approach to optimising buffer conditions to bring homemade lysates up to commercial production potential.

Published
2020
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5. A community effort in SARS‐CoV‐2 drug discovery

Author

Schimunek, Johannes, primary, Seidl, Philipp, additional, Elez, Katarina, additional, Hempel, Tim, additional, Le, Tuan, additional, Noé, Frank, additional, Olsson, Simon, additional, Raich, Lluís, additional, Winter, Robin, additional, Gokcan, Hatice, additional, Gusev, Filipp, additional, Gutkin, Evgeny M., additional, Isayev, Olexandr, additional, Kurnikova, Maria G., additional, Narangoda, Chamali H., additional, Zubatyuk, Roman, additional, Bosko, Ivan P., additional, Furs, Konstantin V., additional, Karpenko, Anna D., additional, Kornoushenko, Yury V., additional, Shuldau, Mikita, additional, Yushkevich, Artsemi, additional, Benabderrahmane, Mohammed, additional, Bousquet-Melou, Patrick, additional, Bureau, Ronan, additional, Charton, Beatrice, additional, Cirou, Bertrand, additional, Gil, Gérard, additional, Allen, William J., additional, Sirimulla, Suman, additional, Watowich, Stanley, additional, Antonopoulos, Nick, additional, Epitropakis, Nikolaos, additional, Krasoulis, Agamemnon, additional, Pitsikalis, Vassilis, additional, Theodorakis, Stavros, additional, Kozlovskii, Igor, additional, Maliutin, Anton, additional, Medvedev, Alexander, additional, Popov, Petr, additional, Zaretckii, Mark, additional, Eghbal-zadeh, Hamid, additional, Halmich, Christina, additional, Hochreiter, Sepp, additional, Mayr, Andreas, additional, Ruch, Peter, additional, Widrich, Michael, additional, Berenger, Francois, additional, Kumar, Ashutosh, additional, Yamanishi, Yoshihiro, additional, Zhang, Kam, additional, Bengio, Emmanuel, additional, Bengio, Yoshua, additional, Jain, Moksh, additional, Korablyov, Maksym, additional, Liu, Cheng-Hao, additional, Gilles, Marcous, additional, Glaab, Enrico, additional, Barnsley, Kelly, additional, Iyengar, Suhasini M., additional, Ondrechen, Mary Jo, additional, Haupt, V. Joachim, additional, Kaiser, Florian, additional, Schroeder, Michael, additional, Pugliese, Luisa, additional, Albani, Simone, additional, Athanasiou, Christina, additional, Beccari, Andrea, additional, Carloni, Paolo, additional, D'Arrigo, Giulia, additional, Gianquinto, Eleonora, additional, Goßen, Jonas, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Kokh, Daria B., additional, Kovachka, Sandra, additional, Manelfi, Candida, additional, Mukherjee, Goutam, additional, Muñiz-Chicharro, Abraham, additional, Musiani, Francesco, additional, Nunes-Alves, Ariane, additional, Paiardi, Giulia, additional, Rossetti, Giulia, additional, Sadiq, S. Kashif, additional, Spyrakis, Francesca, additional, Talarico, Carmine, additional, Tsengenes, Alexandros, additional, Wade, Rebecca, additional, Copeland, Conner, additional, Gaiser, Jeremiah, additional, Olson, Daniel R., additional, Roy, Amitava, additional, Venkatraman, Vishwesh, additional, Wheeler, Travis J., additional, Arthanari, Haribabu, additional, Blaschitz, Klara, additional, Cespugli, Marco, additional, Durmaz, Vedat, additional, Fackeldey, Konstantin, additional, Fischer, Patrick D., additional, Gorgulla, Christoph, additional, Gruber, Christian, additional, Gruber, Karl, additional, Hetmann, Michael, additional, Kinney, Jamie E., additional, Das, Krishna M. Padmanabha, additional, Pandita, Shreya, additional, Singh, Amit, additional, Steinkellner, Georg, additional, Tesseyre, Guilhem, additional, Wagner, Gerhard, additional, Wang, Zi-Fu, additional, Yust, Ryan J., additional, Druzhilovskiy, Dmitry S., additional, Filimonov, Dmitry, additional, Pogodin, Pavel V., additional, Poroikov, Vladimir, additional, Rudik, Anastassia V., additional, Stolbov, Leonid A., additional, Veselovsky, Alexander V., additional, De Rosa, Maria, additional, Simone, Giada De, additional, Gulotta, Maria R., additional, Lombino, Jessica, additional, Mekni, Nedra, additional, Perricone, Ugo, additional, Casini, Arturo, additional, Embree, Amanda, additional, Gordon, D. Benjamin, additional, Lei, David, additional, Pratt, Katelin, additional, Voigt, Christopher A., additional, Chen, Kuang-Yu, additional, Jacob, Yves, additional, Krischuns, Tim, additional, Lafaye, Pierre, additional, Zettor, Agnès, additional, Rodríguez, M. Luis, additional, White, Kris M., additional, Fearon, Daren, additional, von Delft, Frank, additional, Walsh, Martin A., additional, Horvath, Dragos, additional, Brooks, Charles L., additional, Falsafi, Babak, additional, Ford, Bryan, additional, García-Sastre, Adolfo, additional, Lee, Sang Yup, additional, Naffakh, Nadia, additional, Varnek, Alexandre, additional, Klambauer, Guenter, additional, and Hermans, Thomas M., additional

Published
2023
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6. Effective Inhibition of TDP‐43 Aggregation by Native State Stabilization.

Author

Yang, Lixin, Jasiqi, Yllza, Zettor, Agnès, Vadas, Oscar, Chiaravalli, Jeanne, Agou, Fabrice, and Lashuel, Hilal A.

Subjects
TDP-43 proteinopathies, DNA-binding proteins, AMYOTROPHIC lateral sclerosis, HIGH throughput screening (Drug development), NEURODEGENERATION, OLIGONUCLEOTIDES
Abstract

Preventing the misfolding or aggregation of transactive response DNA binding protein with 43 kDa (TDP‐43) is the most actively pursued disease‐modifying strategy to treat amyotrophic lateral sclerosis and other neurodegenerative diseases. In this work, we provide proof of concept that native state stabilization of TDP‐43 is a viable and effective strategy for treating TDP‐43 proteinopathies. Firstly, we leveraged the Cryo‐EM structures of TDP‐43 fibrils to design C‐terminal substitutions that disrupt TDP‐43 aggregation. Secondly, we showed that these substitutions (S333D/S342D) stabilize monomeric TDP‐43 without altering its physiological properties. Thirdly, we demonstrated that binding native oligonucleotide ligands stabilized monomeric TDP‐43 and prevented its fibrillization and phase separation in the absence of direct binding to the aggregation‐prone C‐terminal domain. Fourthly, we showed that the monomeric TDP‐43 variant could be induced to aggregate in a controlled manner, which enabled the design and implementation of a high‐throughput screening assay to identify native state stabilizers of TDP‐43. Altogether, our findings demonstrate that different structural domains in TDP‐43 could be exploited and targeted to develop drugs that stabilize the native state of TDP‐43 and provide a platform to discover novel drugs to treat TDP‐43 proteinopathies. [ABSTRACT FROM AUTHOR]

Published
2024
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7. A community effort to discover small molecule SARS-CoV-2 inhibitors

Author

Schimunek, Johannes, primary, Seidl, Philipp, additional, Elez, Katarina, additional, Hempel, Tim, additional, Le, Tuan, additional, Noé, Frank, additional, Olsson, Simon, additional, Raich, Lluís, additional, Winter, Robin, additional, Gokcan, Hatice, additional, Gusev, Filipp, additional, Gutkin, Evgeny M., additional, Isayev, Olexandr, additional, Kurnikova, Maria G., additional, Narangoda, Chamali H., additional, Zubatyuk, Roman, additional, Bosko, Ivan P., additional, Furs, Konstantin V., additional, Karpenko, Anna D., additional, Kornoushenko, Yury V., additional, Shuldau, Mikita, additional, Yushkevich, Artsemi, additional, Benabderrahmane, Mohammed B., additional, Bousquet-Melou, Patrick, additional, Bureau, Ronan, additional, Charton, Beatrice, additional, Cirou, Bertrand C., additional, Gil, Gérard, additional, Allen, William J., additional, Sirimulla, Suman, additional, Watowich, Stanley, additional, Antonopoulos, Nick A., additional, Epitropakis, Nikolaos E., additional, Krasoulis, Agamemnon K., additional, Pitsikalis, Vassilis P., additional, Theodorakis, Stavros T., additional, Kozlovskii, Igor, additional, Maliutin, Anton, additional, Medvedev, Alexander, additional, Popov, Petr, additional, Zaretckii, Mark, additional, Eghbal-zadeh, Hamid, additional, Halmich, Christina, additional, Hochreiter, Sepp, additional, Mayr, Andreas, additional, Ruch, Peter, additional, Widrich, Michael, additional, Berenger, Francois, additional, Kumar, Ashutosh, additional, Yamanishi, Yoshihiro, additional, Zhang, Kam Y.J., additional, Bengio, Emmanuel, additional, Bengio, Yoshua, additional, Jain, Moksh J., additional, Korablyov, Maksym, additional, Liu, Cheng-Hao, additional, Marcou, Gilles, additional, Glaab, Enrico, additional, Barnsley, Kelly, additional, Iyengar, Suhasini M., additional, Ondrechen, Mary Jo, additional, Haupt, V. Joachim, additional, Kaiser, Florian, additional, Schroeder, Michael, additional, Pugliese, Luisa, additional, Albani, Simone, additional, Athanasiou, Christina, additional, Beccari, Andrea, additional, Carloni, Paolo, additional, D'Arrigo, Giulia, additional, Gianquinto, Eleonora, additional, Goßen, Jonas, additional, Hanke, Anton, additional, Joseph, Benjamin P., additional, Kokh, Daria B., additional, Kovachka, Sandra, additional, Manelfi, Candida, additional, Mukherjee, Goutam, additional, Muñiz-Chicharro, Abraham, additional, Musiani, Francesco, additional, Nunes-Alves, Ariane, additional, Paiardi, Giulia, additional, Rossetti, Giulia, additional, Sadiq, S. Kashif, additional, Spyrakis, Francesca, additional, Talarico, Carmine, additional, Tsengenes, Alexandros, additional, Wade, Rebecca C., additional, Copeland, Conner, additional, Gaiser, Jeremiah, additional, Olson, Daniel R., additional, Roy, Amitava, additional, Venkatraman, Vishwesh, additional, Wheeler, Travis J., additional, Arthanari, Haribabu, additional, Blaschitz, Klara, additional, Cespugli, Marco, additional, Durmaz, Vedat, additional, Fackeldey, Konstantin, additional, Fischer, Patrick D., additional, Gorgulla, Christoph, additional, Gruber, Christian, additional, Gruber, Karl, additional, Hetmann, Michael, additional, Kinney, Jamie E., additional, Padmanabha Das, Krishna M., additional, Pandita, Shreya, additional, Singh, Amit, additional, Steinkellner, Georg, additional, Tesseyre, Guilhem, additional, Wagner, Gerhard, additional, Wang, Zi-Fu, additional, Yust, Ryan J., additional, Druzhilovskiy, Dmitry S., additional, Filimonov, Dmitry A., additional, Pogodin, Pavel V., additional, Poroikov, Vladimir, additional, Rudik, Anastassia V., additional, Stolbov, Leonid A., additional, Veselovsky, Alexander V., additional, De Rosa, Maria, additional, De Simone, Giada, additional, Gulotta, Maria R., additional, Lombino, Jessica, additional, Mekni, Nedra, additional, Perricone, Ugo, additional, Casini, Arturo, additional, Embree, Amanda, additional, Gordon, D. Benjamin, additional, Lei, David, additional, Pratt, Katelin, additional, Voigt, Christopher A., additional, Chen, Kuang-Yu, additional, Jacob, Yves, additional, Krischuns, Tim, additional, Lafaye, Pierre, additional, Zettor, Agnès, additional, Rodríguez, M. Luis, additional, White, Kris M., additional, Fearon, Daren, additional, Von Delft, Frank, additional, Walsh, Martin A., additional, Horvath, Dragos, additional, Brooks III, Charles L., additional, Falsafi, Babak, additional, Ford, Bryan, additional, García-Sastre, Adolfo, additional, Lee, Sang Yup, additional, Naffakh, Nadia, additional, Varnek, Alexandre, additional, Klambauer, Günter, additional, and Hermans, Thomas M., additional

Published
2023
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8. A community effort to discover small molecule SARS-CoV-2 inhibitors

Author

Johannes Schimunek, Philipp Seidl, Katarina Elez, Tim Hempel, Tuan Le, Frank Noé, Simon Olsson, Lluís Raich, Robin Winter, Hatice Gokcan, Filipp Gusev, Evgeny M. Gutkin, Olexandr Isayev, Maria G. Kurnikova, Chamali H. Narangoda, Roman Zubatyuk, Ivan P. Bosko, Konstantin V. Furs, Anna D. Karpenko, Yury V. Kornoushenko, Mikita Shuldau, Artsemi Yushkevich, Mohammed B. Benabderrahmane, Patrick Bousquet-Melou, Ronan Bureau, Beatrice Charton, Bertrand C. Cirou, Gérard Gil, William J. Allen, Suman Sirimulla, Stanley Watowich, Nick A. Antonopoulos, Nikolaos E. Epitropakis, Agamemnon K. Krasoulis, Vassilis P. Pitsikalis, Stavros T. Theodorakis, Igor Kozlovskii, Anton Maliutin, Alexander Medvedev, Petr Popov, Mark Zaretckii, Hamid Eghbal-zadeh, Christina Halmich, Sepp Hochreiter, Andreas Mayr, Peter Ruch, Michael Widrich, Francois Berenger, Ashutosh Kumar, Yoshihiro Yamanishi, Kam Y.J. Zhang, Emmanuel Bengio, Yoshua Bengio, Moksh J. Jain, Maksym Korablyov, Cheng-Hao Liu, Gilles Marcou, Enrico Glaab, Kelly Barnsley, Suhasini M. Iyengar, Mary Jo Ondrechen, V. Joachim Haupt, Florian Kaiser, Michael Schroeder, Luisa Pugliese, Simone Albani, Christina Athanasiou, Andrea Beccari, Paolo Carloni, Giulia D'Arrigo, Eleonora Gianquinto, Jonas Goßen, Anton Hanke, Benjamin P. Joseph, Daria B. Kokh, Sandra Kovachka, Candida Manelfi, Goutam Mukherjee, Abraham Muñiz-Chicharro, Francesco Musiani, Ariane Nunes-Alves, Giulia Paiardi, Giulia Rossetti, S. Kashif Sadiq, Francesca Spyrakis, Carmine Talarico, Alexandros Tsengenes, Rebecca C. Wade, Conner Copeland, Jeremiah Gaiser, Daniel R. Olson, Amitava Roy, Vishwesh Venkatraman, Travis J. Wheeler, Haribabu Arthanari, Klara Blaschitz, Marco Cespugli, Vedat Durmaz, Konstantin Fackeldey, Patrick D. Fischer, Christoph Gorgulla, Christian Gruber, Karl Gruber, Michael Hetmann, Jamie E. Kinney, Krishna M. Padmanabha Das, Shreya Pandita, Amit Singh, Georg Steinkellner, Guilhem Tesseyre, Gerhard Wagner, Zi-Fu Wang, Ryan J. Yust, Dmitry S. Druzhilovskiy, Dmitry A. Filimonov, Pavel V. Pogodin, Vladimir Poroikov, Anastassia V. Rudik, Leonid A. Stolbov, Alexander V. Veselovsky, Maria De Rosa, Giada De Simone, Maria R. Gulotta, Jessica Lombino, Nedra Mekni, Ugo Perricone, Arturo Casini, Amanda Embree, D. Benjamin Gordon, David Lei, Katelin Pratt, Christopher A. Voigt, Kuang-Yu Chen, Yves Jacob, Tim Krischuns, Pierre Lafaye, Agnès Zettor, M. Luis Rodríguez, Kris M. White, Daren Fearon, Frank Von Delft, Martin A. Walsh, Dragos Horvath, Charles L. Brooks III, Babak Falsafi, Bryan Ford, Adolfo García-Sastre, Sang Yup Lee, Nadia Naffakh, Alexandre Varnek, Günter Klambauer, and Thomas M. Hermans

Abstract

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of a community effort, the “Billion molecules against Covid-19 challenge”, to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 potentially active molecules, which were subsequently ranked to find ‘consensus compounds’. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (Nsp12 domain), and (alpha) spike protein S. Overall, 27 potential inhibitors were experimentally confirmed by binding-, cleavage-, and/or viral suppression assays and are presented here. All results are freely available and can be taken further downstream without IP restrictions. Overall, we show the effectiveness of computational techniques, community efforts, and communication across research fields (i.e., protein expression and crystallography, in silico modeling, synthesis and biological assays) to accelerate the early phases of drug discovery.

Published
2023
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11. A highly sensitive cell-based luciferase assay for high-throughput automated screening of SARS-CoV-2 nsp5/3CLpro inhibitors

Author

K.Y. Chen, T. Krischuns, L. Ortega Varga, E. Harigua-Souiai, S. Paisant, A. Zettor, J. Chiaravalli, A. Delpal, D. Courtney, A. O'Brien, S.C. Baker, E. Decroly, C. Isel, F. Agou, Y. Jacob, A. Blondel, N. Naffakh, Biologie des ARN et virus influenza - RNA Biology of Influenza Virus (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Loyola University [Chicago], Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur. KYC and TK were funded by the Agence Nationale de la Recherche (grants ANR-18-CE18-0026, ANR-18-CE18-0028 and ANR-10-LABX-62-IBEID). LOV received financial support from the Agence Nationale de la Recherche (ANR-17-CE11-0030, ANR-19-CE18-0010) and by the 'URGENCE COVID-19' campaign. EHS is financially supported by the programs of the Ministry of Higher Education and Research of the Republic of Tunisia. DC was funded by Marie Slodowska Curie Global Fellowship MSCA-IF-GF:747810. AZ, JC and FA received financial support from the Technological Transfer Office of Institut Pasteur (DARRI). ED and AD received financial support from the European Union's Horizon 2020 Research and Innovation program under grant N°101003627 H2020 10 + 8 (CARE project). AO and SCB were supported in part by a grant from the National Institutes of Health, USA (R01 AI085089 and R01 AI159945)., We thank Nicholas Heaton (Duke University), Rolf Hilgenfeld (University of Luebeck), Olivier Schwartz, Sylvie van der Werf, Olivier Sperandio and Guillaume Bouvier (all from Institut Pasteur) for providing biological material and advice. We thank Marine Ghazarian (Institut Pasteur) for technical help, Yves Janin (Institut Pasteur) for providing reagents and for insightful suggestions on the manuscript, and Mallory Perrin-Wolff (Institut Pasteur) for her continuous support., ANR-18-CE18-0026,microFLU-REASSORT,Analyse à haut-débit du réassortiment entre virus influenza A par microfluidique et séquençage du génome ARN de virus uniques - application à l'analyse du risque pandémique et à l'optimisation des virus candidats vaccins(2018), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-17-CE11-0030,NICOFIVE,Découverte de modulateurs allostériques ciblant les récepteurs nicotiniques alpha5(2017), ANR-19-CE18-0010,SPIM,Synthèse, biologie et structure pour guider l'optimisation d'Inhibiteurs de la peptidase SUB1 de Plasmodium, une cible potentielle pour le traitement du paludisme(2019), and European Project: 101003627,H2020-EU.3.1. - SOCIETAL CHALLENGES - Health, demographic change and well-being,SCORE(2020)

Subjects
Pharmacology, Small molecule inhibitors, Viral Proteases, SARS-CoV-2, High-throughput screening, 3CLpro, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Antiviral Agents, Article, COVID-19 Drug Treatment, Molecular Docking Simulation, Virology, nsp5, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Humans, Cell-based assay, Protease Inhibitors, Luciferases, Peptide Hydrolases
Abstract

Effective drugs against SARS-CoV-2 are urgently needed to treat severe cases of infection and for prophylactic use. The main viral protease (nsp5 or 3CLpro) represents an attractive and possibly broad-spectrum target for drug development as it is essential to the virus life cycle and highly conserved among betacoronaviruses. Sensitive and efficient high-throughput screening methods are key for drug discovery. Here we report the development of a gain-of-signal, highly sensitive cell-based luciferase assay to monitor SARS-CoV-2 nsp5 activity and show that it is suitable for high-throughput screening of compounds in a 384-well format. A benefit of miniaturisation and automation is that screening can be performed in parallel on a wild-type and a catalytically inactive nsp5, which improves the selectivity of the assay. We performed molecular docking-based screening on a set of 14,468 compounds from an in-house chemical database, selected 359 candidate nsp5 inhibitors and tested them experimentally. We identified four molecules, including the broad-spectrum antiviral merimepodib/VX-497, which show anti-nsp5 activity and inhibit SARS-CoV-2 replication in A549-ACE2 cells with IC50 values in the 4-21 µM range. The here described assay will allow the screening of large-scale compound libraries for SARS-CoV-2 nsp5 inhibitors. Moreover, we provide evidence that this assay can be adapted to other coronaviruses and viruses which rely on a viral protease.

Published
2021
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12. A highly sensitive cell-based luciferase assay for high-throughput automated screening of SARS-CoV-2 nsp5/3CLpro inhibitors

Author

Chen, KY, primary, Krischuns, T, additional, Varga, L Ortega, additional, Harigua-Souiai, E, additional, Paisant, S, additional, Zettor, A, additional, Chiaravalli, J, additional, Courtney, D, additional, O’Brien, A, additional, Baker, SC, additional, Isel, C, additional, Agou, F, additional, Jacob, Y, additional, Blondel, A, additional, and Naffakh, N, additional

Published
2021
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13. Killer bee molecules: antimicrobial peptides as effector molecules to target sporogonic stages of Plasmodium.

Author

Victoria Carter, Ann Underhill, Ibrahima Baber, Lakamy Sylla, Mounirou Baby, Isabelle Larget-Thiery, Agnès Zettor, Catherine Bourgouin, Ulo Langel, Ingrid Faye, Laszlo Otvos, John D Wade, Mamadou B Coulibaly, Sekou F Traore, Frederic Tripet, Paul Eggleston, and Hilary Hurd

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

A new generation of strategies is evolving that aim to block malaria transmission by employing genetically modified vectors or mosquito pathogens or symbionts that express anti-parasite molecules. Whilst transgenic technologies have advanced rapidly, there is still a paucity of effector molecules with potent anti-malaria activity whose expression does not cause detrimental effects on mosquito fitness. Our objective was to examine a wide range of antimicrobial peptides (AMPs) for their toxic effects on Plasmodium and anopheline mosquitoes. Specifically targeting early sporogonic stages, we initially screened AMPs for toxicity against a mosquito cell line and P. berghei ookinetes. Promising candidate AMPs were fed to mosquitoes to monitor adverse fitness effects, and their efficacy in blocking rodent malaria infection in Anopheles stephensi was assessed. This was followed by tests to determine their activity against P. falciparum in An. gambiae, initially using laboratory cultures to infect mosquitoes, then culminating in preliminary assays in the field using gametocytes and mosquitoes collected from the same area in Mali, West Africa. From a range of 33 molecules, six AMPs able to block Plasmodium development were identified: Anoplin, Duramycin, Mastoparan X, Melittin, TP10 and Vida3. With the exception of Anoplin and Mastoparan X, these AMPs were also toxic to an An. gambiae cell line at a concentration of 25 µM. However, when tested in mosquito blood feeds, they did not reduce mosquito longevity or egg production at concentrations of 50 µM. Peptides effective against cultured ookinetes were less effective when tested in vivo and differences in efficacy against P. berghei and P. falciparum were seen. From the range of molecules tested, the majority of effective AMPs were derived from bee/wasp venoms.

Published
2013
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14. Diverged alleles of the Anopheles gambiae leucine-rich repeat gene APL1A display distinct protective profiles against Plasmodium falciparum.

Author

Inge Holm, Catherine Lavazec, Thierry Garnier, Christian Mitri, Michelle M Riehle, Emmanuel Bischoff, Emma Brito-Fravallo, Eizo Takashima, Isabelle Thiery, Agnes Zettor, Stephane Petres, Catherine Bourgouin, Kenneth D Vernick, and Karin Eiglmeier

Subjects
Medicine, Science
Abstract

Functional studies have demonstrated a role for the Anopheles gambiae APL1A gene in resistance against the human malaria parasite, Plasmodium falciparum. Here, we exhaustively characterize the structure of the APL1 locus and show that three structurally different APL1A alleles segregate in the Ngousso colony. Genetic association combined with RNAi-mediated gene silencing revealed that APL1A alleles display distinct protective profiles against P. falciparum. One APL1A allele is sufficient to explain the protective phenotype of APL1A observed in silencing experiments. Epitope-tagged APL1A isoforms expressed in an in vitro hemocyte-like cell system showed that under assay conditions, the most protective APL1A isoform (APL1A(2)) localizes within large cytoplasmic vesicles, is not constitutively secreted, and forms only one protein complex, while a less protective isoform (APL1A(1)) is constitutively secreted in at least two protein complexes. The tested alleles are identical to natural variants in the wild A. gambiae population, suggesting that APL1A genetic variation could be a factor underlying natural heterogeneity of vector susceptibility to P. falciparum.

Published
2012
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16. Large scale active-learning-guided exploration to maximize cell-free production

Author

Paul Soudier, Mathilde Koch, Angelo Cardoso Batista, Amir Pandi, Jean-Loup Faulon, Agnès Zettor, and Olivier Borkowski

Subjects
0106 biological sciences, 0303 health sciences, Active learning (machine learning), Computer science, Scale (chemistry), media_common.quotation_subject, Cell free, 01 natural sciences, 03 medical and health sciences, 010608 biotechnology, Gene expression, Protein biosynthesis, Production (economics), Quality (business), Biochemical engineering, Productivity, 030304 developmental biology, media_common
Abstract

Lysate-based cell-free systems have become a major platform to study gene expression but batch-to-batch variation makes protein production difficult to predict. Here we describe an active learning approach to explore a combinatorial space of ~4,000,000 cell-free compositions, maximizing protein production and identifying critical parameters involved in cell-free productivity. We also provide a one-step-method to achieve high quality predictions for protein production using minimal experimental effort regardless of the lysate quality.

Published
2019
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18. De l'usage traditionnel de la papaye à l'albendazole, la prise en charge des parasitoses digestives à l'Île de La Réunion

Author

Zettor, Doriane and UB -, Odonto

Subjects
[SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Parasitologie, Papaye, Anti parasitaires, Albendazole, Ile de la Réunion
Abstract

L’île de La Réunion est un territoire français ayant un climat tropical, ainsi les maladies comme les parasitoses digestives sont toujours présentes même si leurs nombres diminuent depuis plusieurs décennies. Cette société réunionnaise s’est construite sur le partage et l’enrichissement de ses traditions venues de diverses cultures (malgaches, indiennes, africaines, chinoises) avec l’utilisation de la flore locale qu’elle soit importée ou endémique, pouvant être mêlées à des pratiques magico-spirituelles. L’utilisation des plantes est commune sur l’île pour soigner les maux du quotidien. ; ainsi traiter les parasitoses par celles-ci n’est pas une exception. On peut alors décrire des plantes dont le nom est évocateur comme l’Herbe à vers ou d’autres dont l’utilisation quasi-quotidienne de celle-ci peut nous surprendre. Les antiparasitaires, mis sur le marché depuis les années 1980, sont toujours très utilisés même de nos jours. Ils sont prescrits aux enfants majoritairement avec une différence avec les pratiques faites en France métropolitaine. Alors que les parasitoses digestives sont de moins en moins nombreuses, et les délivrances d’antiparasitaires qui restent assez importantes, cela apporte une vision de la société réunionnaise très attachée à ses traditions.

Published
2019

19. Anopheles plumbeus (Diptera: Culicidae) in Europe: a mere nuisance mosquito or potential malaria vector?

Author

Schaffner Francis, Thiéry Isabelle, Kaufmann Christian, Zettor Agnès, Lengeler Christian, Mathis Alexander, and Bourgouin Catherine

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Anopheles plumbeus has been recognized as a minor vector for human malaria in Europe since the beginning of the 20th century. In recent years this tree hole breeding mosquito species appears to have exploited novel breeding sites, including large and organically rich man-made containers, with consequently larger mosquito populations in close vicinity to humans. This lead to investigate whether current populations of An. plumbeus would be able to efficiently transmit Plasmodium falciparum, the parasite responsible for the most deadly form of malaria. Methods Anopheles plumbeus immatures were collected from a liquid manure pit in Switzerland and transferred as adults to the CEPIA (Institut Pasteur, France) where they were fed on P. falciparum gametocytes produced in vitro. Anopheles gambiae mosquitoes served as controls. Development of P. falciparum in both mosquito species was followed by microscopical detection of oocysts on mosquito midguts and by sporozoite detection in the head/thorax by PCR and microscopy. Results A total of 293 wild An. plumbeus females from four independent collections successfully fed through a membrane on blood containing P. falciparum gametocytes. Oocysts were observed in mosquito midguts and P. falciparum DNA was detected in head-thorax samples in all four experiments, demonstrating, on a large mosquito sample, that An. plumbeus is indeed receptive to P. falciparum NF54 and able to produce sporozoites. Importantly, the proportion of sporozoites-infected An. plumbeus was almost similar to that of An. gambiae (31 to 88% An. plumbeus versus 67 to 97% An. gambiae). However, the number of sporozoites produced was significantly lower in infected An. plumbeus. Conclusion The results show that a sample of field-caught An. plumbeus has a moderate to high receptivity towards P. falciparum. Considering the increased mobility of humans between Europe and malaria endemic countries and changes in environment and climate, these data strongly suggest that An. plumbeus could act as a vector for malaria and thus significantly contribute to increasing the malaria transmission risk in Central-Western Europe. In locations showing high vulnerability to the presence of gametocyte carriers, the risk of transmission of malaria by An. plumbeus should be considered.

Published
2012
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21. In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo

Author

Rogier Christophe, Amalvict Rémy, Baret Eric, Castello Jacky, Zettor Agnès, Hovette Philippe, Bogreau Hervé, Pelleau Stéphane, Briolant Sébastien, and Pradines Bruno

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Quinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases. Investigations into the genetic basis for quinine resistance (QNR) suggest that QNR is complex and involves several genes, with either an additive or a pairwise effect. The results obtained when assessing one of these genes, the plasmodial Na+/H+ exchanger, Pfnhe-1, were found to depend upon the geographic origin of the parasite strain. Most of the associations identified have been made in Asian strains; in contrast, in African strains, the influence of Pfnhe on QNR is not apparent. However, a recent study carried out in Kenya did show a significant association between a Pfnhe polymorphism and QNR. As genetic differences may exist across the African continent, more field data are needed to determine if this association exists in other African regions. In the present study, association between Pfnhe and QNR is investigated in a series of isolates from central Africa. Methods The sequence analysis of the polymorphisms at the Pfnhe-1 ms4760 microsatellite and the evaluation of in vitro quinine susceptibility (by isotopic assay) were conducted in 74 P. falciparum isolates from the Republic of Congo. Results Polymorphisms in the number of DNNND or NHNDNHNNDDD repeats in the Pfnhe-1 ms4760 microsatellite were not associated with quinine susceptibility. Conclusions The polymorphism in the microsatellite ms4760 in Pfnhe-1 that cannot be used to monitor quinine response in the regions of the Republic of Congo, where the isolates came from. This finding suggests that there exists a genetic background associated with geographic area for the association that will prevent the use of Pfnhe as a molecular marker for QNR. The contribution of Pfnhe to the in vitro response to quinine remains to be assessed in other regions, including in countries with different levels of drug pressure.

Published
2011
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22. Transgenic Anopheles stephensi coexpressing single-chain antibodies resist Plasmodium falciparum development

Author

Anthony A. James, Nijole Jasinskiene, Isabelle Thiery, Agnès Zettor, Catherine Bourgouin, Mikhail Tretiakov, Alison T. Isaacs, University of California [Irvine] (UCI), University of California, Centre de Production et Infection des Anophèles (plateforme) - Center for the Production and Infection of Anopheles (platform) (CEPIA), Institut Pasteur [Paris], Génétique et Génomique des Insectes vecteurs, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The authors are grateful to Aniko Fazekas, Rebeca Juarez, and Trung Dinh for mosquito husbandry. Research was supported by grants from the NIH NIAID (AI29746) to A.A.J. and from the Institut Pasteur to C.B. In part, A.I. was supported by a Chateaubriand pre-doctoral fellowship from the Embassy of France in the United States., University of California [Irvine] (UC Irvine), University of California (UC), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Sporozoites, Animals, Genetically Modified, 0302 clinical medicine, Plasmid, MESH: Gene Expression Regulation, Developmental, Parasite hosting, MESH: Animals, MESH: Models, Genetic, MESH: In Situ Hybridization, Fluorescence, Transgenes, MESH: Plasmodium falciparum, In Situ Hybridization, Fluorescence, MESH: Single-Chain Antibodies, 0303 health sciences, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Gene Expression Regulation, Developmental, MESH: Gene Expression Regulation, 3. Good health, Circumsporozoite protein, PNAS Plus, Sporozoites, MESH: Genetic Engineering, Female, Genetic Engineering, Plasmids, Transgene, 030231 tropical medicine, Plasmodium falciparum, MESH: Transgenes, Biology, MESH: Animals, Genetically Modified, MESH: Anopheles, 03 medical and health sciences, MESH: Plasmids, parasitic diseases, Anopheles, Animals, Gene, Anopheles stephensi, 030304 developmental biology, Binding Sites, Models, Genetic, biology.organism_classification, Virology, MESH: Male, Culicidae, MESH: Binding Sites, Gene Expression Regulation, MESH: Culicidae, MESH: Female, Single-Chain Antibodies
Abstract

Anopheles stephensi mosquitoes expressing m1C3, m4B7, or m2A10 single-chain antibodies (scFvs) have significantly lower levels of infection compared to controls when challenged with Plasmodium falciparum , a human malaria pathogen. These scFvs are derived from antibodies specific to a parasite chitinase, the 25 kDa protein and the circumsporozoite protein, respectively. Transgenes comprising m2A10 in combination with either m1C3 or m4B7 were inserted into previously-characterized mosquito chromosomal “docking” sites using site-specific recombination. Transgene expression was evaluated at four different genomic locations and a docking site that permitted tissue- and sex-specific expression was researched further. Fitness studies of docking site and dual scFv transgene strains detected only one significant fitness cost: adult docking-site males displayed a late-onset reduction in survival. The m4B7/m2A10 mosquitoes challenged with P. falciparum had few or no sporozoites, the parasite stage infective to humans, in three of four experiments. No sporozoites were detected in m1C3/m2A10 mosquitoes in challenge experiments when both genes were induced at developmentally relevant times. These studies support the conclusion that expression of a single copy of a dual scFv transgene can completely inhibit parasite development without imposing a fitness cost on the mosquito.

Published
2012
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23. Diverged alleles of the Anopheles gambiae leucine-rich repeat gene APL1A display distinct protective profiles against Plasmodium falciparum

Author

Emmanuel Bischoff, Agnès Zettor, Kenneth D. Vernick, Karin Eiglmeier, Eizo Takashima, Christian Mitri, Thierry Garnier, Emma Brito-Fravallo, Stéphane Petres, Inge Holm, Isabelle Thiery, Catherine Lavazec, Catherine Bourgouin, Michelle M. Riehle, Génétique et Génomique des Insectes vecteurs, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Production et Infection des Anophèles (plateforme) - Center for the Production and Infection of Anopheles (platform) (CEPIA), Institut Pasteur [Paris], Production de Protéines Recombinantes et d'Anticorps (Plate-Forme), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
Anopheles gambiae, lcsh:Medicine, Genes, Insect, Mosquitoes, Gene Order, Natural Selection, Genetics of the Immune System, lcsh:Science, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, biology, 030302 biochemistry & molecular biology, Genes, Anopheles/*genetics/immunology/parasitology, Gene Pool, Innate Immunity, 3. Good health, Host-Pathogen Interaction, Alleles, Protein Transport, Infectious Diseases, Medicine, Research Article, Gene isoform, Immunology, Plasmodium falciparum, Population, Molecular Sequence Data, Quantitative Trait Loci, Locus (genetics), Microbiology, 03 medical and health sciences, Plasmodium falciparum/immunology, Anopheles, Genetic variation, parasitic diseases, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Gene Silencing, Amino Acid Sequence, Allele, education, Biology, Gene, 030304 developmental biology, lcsh:R, Immunity, Computational Biology, Tropical Diseases (Non-Neglected), Vectors and Hosts, biology.organism_classification, Molecular biology, Malaria, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, Haplotypes, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Insect, Sequence Alignment, Population Genetics
Abstract

International audience; Functional studies have demonstrated a role for the Anopheles gambiae APL1A gene in resistance against the human malaria parasite, Plasmodium falciparum. Here, we exhaustively characterize the structure of the APL1 locus and show that three structurally different APL1A alleles segregate in the Ngousso colony. Genetic association combined with RNAi-mediated gene silencing revealed that APL1A alleles display distinct protective profiles against P. falciparum. One APL1A allele is sufficient to explain the protective phenotype of APL1A observed in silencing experiments. Epitope-tagged APL1A isoforms expressed in an in vitro hemocyte-like cell system showed that under assay conditions, the most protective APL1A isoform (APL1A(2)) localizes within large cytoplasmic vesicles, is not constitutively secreted, and forms only one protein complex, while a less protective isoform (APL1A(1)) is constitutively secreted in at least two protein complexes. The tested alleles are identical to natural variants in the wild A. gambiae population, suggesting that APL1A genetic variation could be a factor underlying natural heterogeneity of vector susceptibility to P. falciparum.

Published
2012
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24. A community effort in SARS‐CoV‐2 drug discovery

Author

Schimunek, Johannes, Seidl, Philipp, Elez, Katarina, Hempel, Tim, Le, Tuan, Noé, Frank, Olsson, Simon, Raich, Lluís, Winter, Robin, Gokcan, Hatice, Gusev, Filipp, Gutkin, Evgeny M., Isayev, Olexandr, Kurnikova, Maria G., Narangoda, Chamali H., Zubatyuk, Roman, Bosko, Ivan P., Furs, Konstantin V., Karpenko, Anna D., Kornoushenko, Yury V., Shuldau, Mikita, Yushkevich, Artsemi, Benabderrahmane, Mohammed B., Bousquet‐Melou, Patrick, Bureau, Ronan, Charton, Beatrice, Cirou, Bertrand C., Gil, Gérard, Allen, William J., Sirimulla, Suman, Watowich, Stanley, Antonopoulos, Nick, Epitropakis, Nikolaos, Krasoulis, Agamemnon, Itsikalis, Vassilis, Theodorakis, Stavros, Kozlovskii, Igor, Maliutin, Anton, Medvedev, Alexander, Popov, Petr, Zaretckii, Mark, Eghbal‐Zadeh, Hamid, Halmich, Christina, Hochreiter, Sepp, Mayr, Andreas, Ruch, Peter, Widrich, Michael, Berenger, Francois, Kumar, Ashutosh, Yamanishi, Yoshihiro, Zhang, Kam Y. J., Bengio, Emmanuel, Bengio, Yoshua, Jain, Moksh J., Korablyov, Maksym, Liu, Cheng‐Hao, Marcou, Gilles, Glaab, Enrico, Barnsley, Kelly, Iyengar, Suhasini M., Ondrechen, Mary Jo, Haupt, V. Joachim, Kaiser, Florian, Schroeder, Michael, Pugliese, Luisa, Albani, Simone, Athanasiou, Christina, Beccari, Andrea, Carloni, Paolo, D'Arrigo, Giulia, Gianquinto, Eleonora, Goßen, Jonas, Hanke, Anton, Joseph, Benjamin P., Kokh, Daria B., Kovachka, Sandra, Manelfi, Candida, Mukherjee, Goutam, Muñiz‐Chicharro, Abraham, Musiani, Francesco, Nunes‐Alves, Ariane, Paiardi, Giulia, Rossetti, Giulia, Sadiq, S. Kashif, Spyrakis, Francesca, Talarico, Carmine, Tsengenes, Alexandros, Wade, Rebecca C., Copeland, Conner, Gaiser, Jeremiah, Olson, Daniel R., Roy, Amitava, Venkatraman, Vishwesh, Wheeler, Travis J., Arthanari, Haribabu, Blaschitz, Klara, Cespugli, Marco, Durmaz, Vedat, Fackeldey, Konstantin, Fischer, Patrick D., Gorgulla, Christoph, Gruber, Christian, Gruber, Karl, Hetmann, Michael, Kinney, Jamie E., Padmanabha Das, Krishna M., Pandita, Shreya, Singh, Amit, Steinkellner, Georg, Tesseyre, Guilhem, Wagner, Gerhard, Wang, Zi‐Fu, Yust, Ryan J., Druzhilovskiy, Dmitry S., Filimonov, Dmitry A., Pogodin, Pavel V., Poroikov, Vladimir, Rudik, Anastassia V., Stolbov, Leonid A., Veselovsky, Alexander V., De Rosa, Maria, De Simone, Giada, Gulotta, Maria R., Lombino, Jessica, Mekni, Nedra, Perricone, Ugo, Casini, Arturo, Embree, Amanda, Gordon, D. Benjamin, Lei, David, Pratt, Katelin, Voigt, Christopher A., Chen, Kuang‐Yu, Jacob, Yves, Krischuns, Tim, Lafaye, Pierre, Zettor, Agnès, Rodríguez, M. Luis, White, Kris M., Fearon, Daren, Von Delft, Frank, Walsh, Martin A., Horvath, Dragos, Brooks, Charles L., Falsafi, Babak, Ford, Bryan, García‐Sastre, Adolfo, Yup Lee, Sang, Naffakh, Nadia, Varnek, Alexandre, Klambauer, Günter, and Hermans, Thomas M.

Abstract

The COVID‐19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small‐molecule drugs that are widely available, including in low‐ and middle‐income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the “Billion molecules against COVID‐19 challenge”, to identify small‐molecule inhibitors against SARS‐CoV‐2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find ‘consensus compounds’. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding‐, cleavage‐, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS‐CoV‐2 treatments.

Published
2024
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25. Susceptibility of Plasmodium falciparum isolates to doxycycline is associated with pftetQ sequence polymorphisms and pftetQ and pfmdt copy numbers

Author

Sébastien Briolant, Christophe Rogier, Nathalie Wurtz, Agnès Zettor, and Bruno Pradines

Subjects
DNA Copy Number Variations, Plasmodium falciparum, Drug Resistance, Drug resistance, Biology, Polymorphism, Single Nucleotide, law.invention, Bacterial Proteins, law, medicine, Immunology and Allergy, Humans, Insertion sequence, Polymerase chain reaction, Antibacterial agent, Doxycycline, Quinine, biology.organism_classification, medicine.disease, Virology, Infectious Diseases, Genes, MDR, Malaria, medicine.drug
Abstract

Background. Doxycycline is used in combination with quinine for malaria treatment or alone for malaria chemoprophylaxis. However, the occurrence of malaria after doxycycline chemoprophylaxis has been reported. Identification of genetic determinants that contribute to the susceptibility of Plasmodium falciparum to doxycycline will be important for the detection and surveillance of doxycycline resistance. Methods. Sequence analysis of 11 genes (pftufA, pfEF-TS, pfmdt, pftetQ, pfrps3, pfrps7, pfrps8, pfrps9, pfrps11, pfrps14, and pfrps17) and evaluation of pfmdt and pftetQ copy numbers by quantitative real-time polymerase chain reaction were conducted in 90 African P. falciparum isolates that were obtained from 14 countries and that belonged to phenotypic groups differing in their doxycycline median inhibitory concentrations. Results. We found that pfmdt copy number of >1 (adjusted odds ratio [OR], 7.09 [95% confidence interval {CI}, 1.58-31.82]; P = .011), pftetQ copy number of >1 (adjusted OR, 5.23 [95% CI, 1.06-25.77]; P = .042), and KYNNNN amino acid motif repeats of

Published
2009

26. Plasmodium falciparum Na+/H+ Exchanger 1 Transporter Is Involved in Reduced Susceptibility to Quinine ▿

Author

Maud Henry, Bruno Pradines, Joel Mosnier, Sébastien Briolant, Meïli Baragatti, Christophe Rogier, Eric Baret, Agnès Zettor, Thierry Fusai, Stéphane Pelleau, and Rémy Amalvict

Subjects
Sodium-Hydrogen Exchangers, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Context (language use), Drug resistance, Biology, Antimalarials, Parasitic Sensitivity Tests, Mechanisms of Resistance, parasitic diseases, medicine, Animals, Humans, Pharmacology (medical), Artemisinin, Malaria, Falciparum, Pharmacology, Genetics, Quinine, Polymorphism, Genetic, Clindamycin, medicine.disease, biology.organism_classification, Multiple drug resistance, Infectious Diseases, Malaria, medicine.drug, Microsatellite Repeats
Abstract

Malaria is the most important parasitic disease in the world, affecting 300 to 500 million people and killing 3 million people every year. Quinine (QN) has been used as a malaria treatment for more than 350 years in Africa, with little emergence and spread of resistance. QN remains the first-line antimalarial drug for the treatment of complicated malaria in Europe and Africa. However, despite QN′s efficacy against chloroquine-resistant strains, the emergence of QN resistance (QNR) has been documented. The first cases of QN clinical failure were observed in Brazil and Asia in the 1960s (4, 12). In the 1980s, clinical failures became more frequent in Southeast Asia, South America, and Africa (13, 15, 19, 22, 33). However, QNR is not yet a significant problem. QN remains the first-line drug for severe malaria and remains widely used at present as a second-line therapy for uncomplicated malaria in Africa and other areas. Artemisinin-based combination therapies were proposed as a first-line treatment for uncomplicated malaria 6 years ago. Since 2001, more than 56 countries have officially adopted artemisinin-based combination therapies for the treatment of Plasmodium falciparum malaria. However, individual P. falciparum isolates that are resistant to artemisinin in vitro in Cambodia have been described (14, 21). It is not clear whether these strains are associated with clinical failures. One strategy that health officials can pursue to reduce the prevalence of malaria is to combine QN with other antimalarial drugs such as tetracycline (8, 18) or clindamycin (16). Although some reports of treatment failure of QN exist, it is difficult to fully document QNR because of its short elimination half-life, the requirement to administer the drug three times a day for at least 5 days, drug intolerance often leading to poor compliance, and the lack of reliable data on the correlation between QN 50% inhibitory concentrations (IC50s) and clinical failure. Maximizing the efficacy and longevity of QN as a tool for malaria control will depend critically on pursuing intensive research into identifying in vitro markers as well as implementing in vitro and in vivo surveillance programs such as those championed by the World Antimalarial Resistance Network (30, 31). In this context, there is a need to identify molecular markers that predict QNR and that can provide an active surveillance method to monitor temporal trends in parasite susceptibility (23). QNR appears to share common characteristics with chloroquine resistance. QNR is associated with mutations in both the P. falciparum multidrug resistance gene mdr1 (Pfmdr1) (20, 26) and the chloroquine resistance transporter gene Pfcrt (6, 7, 20). Nevertheless, the mechanism of QNR is still unclear. In addition to Pfmdr1 and Pfcrt, other genetic polymorphisms such as variations in microsatellite length on the sodium/hydrogen exchanger gene Pfnhe-1 (11) and mutations on the multidrug resistance protein gene Pfmrp might contribute to QNR (20). The evidence for the involvement of Pfnhe-1 or Pfmrp in QNR is limited. Only one previous study investigated the association of QN IC50 and polymorphisms in the Pfnhe-1 gene in P. falciparum isolates (11). The objective of the present study was to investigate genetic polymorphisms in Pfcrt, Pfmrp, Pfmdr1, and Pfnhe-1 that could be associated with QNR in order to identify molecular markers of QNR that could be used for surveillance of resistance.

Published
2009

27. Killer bee molecules : antimicrobial peptides as effector molecules to target sporogonic stages of Plasmodium

Author

Carter, Victoria, Underhill, Ann, Baber, Ibrahima, Sylla, Lakamy, Baby, Mounirou, Larget-Thiery, Isabelle, Zettor, Agnès, Bourgouin, Catherine, Langel, Ülo, Faye, Ingrid, Otvos, Laszlo, Wade, John D., Coulibaly, Mamadou B., Traore, Sekou F., Tripet, Frederic, Eggleston, Paul, Hurd, Hilary, Carter, Victoria, Underhill, Ann, Baber, Ibrahima, Sylla, Lakamy, Baby, Mounirou, Larget-Thiery, Isabelle, Zettor, Agnès, Bourgouin, Catherine, Langel, Ülo, Faye, Ingrid, Otvos, Laszlo, Wade, John D., Coulibaly, Mamadou B., Traore, Sekou F., Tripet, Frederic, Eggleston, Paul, and Hurd, Hilary

Abstract

A new generation of strategies is evolving that aim to block malaria transmission by employing genetically modified vectors or mosquito pathogens or symbionts that express anti-parasite molecules. Whilst transgenic technologies have advanced rapidly, there is still a paucity of effector molecules with potent anti-malaria activity whose expression does not cause detrimental effects on mosquito fitness. Our objective was to examine a wide range of antimicrobial peptides (AMPs) for their toxic effects on Plasmodium and anopheline mosquitoes. Specifically targeting early sporogonic stages, we initially screened AMPs for toxicity against a mosquito cell line and P. berghei ookinetes. Promising candidate AMPs were fed to mosquitoes to monitor adverse fitness effects, and their efficacy in blocking rodent malaria infection in Anopheles stephensi was assessed. This was followed by tests to determine their activity against P. falciparum in An. gambiae, initially using laboratory cultures to infect mosquitoes, then culminating in preliminary assays in the field using gametocytes and mosquitoes collected from the same area in Mali, West Africa. From a range of 33 molecules, six AMPs able to block Plasmodium development were identified: Anoplin, Duramycin, Mastoparan X, Melittin, TP10 and Vida3. With the exception of Anoplin and Mastoparan X, these AMPs were also toxic to an An. gambiae cell line at a concentration of 25 µM. However, when tested in mosquito blood feeds, they did not reduce mosquito longevity or egg production at concentrations of 50 µM. Peptides effective against cultured ookinetes were less effective when tested in vivo and differences in efficacy against P. berghei and P. falciparum were seen. From the range of molecules tested, the majority of effective AMPs were derived from bee/wasp venoms., AuthorCount: 17

Published
2013
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28. Killer Bee Molecules: Antimicrobial Peptides as Effector Molecules to Target Sporogonic Stages of Plasmodium

Author

Schneider, DS, Carter, V, Underhill, A, Baber, I, Sylla, L, Baby, M, Larget-Thiery, I, Zettor, A, Bourgouin, C, Langel, U, Faye, I, Otvos, L, Wade, JD, Coulibaly, MB, Traore, SF, Tripet, F, Eggleston, P, Hurd, H, Schneider, DS, Carter, V, Underhill, A, Baber, I, Sylla, L, Baby, M, Larget-Thiery, I, Zettor, A, Bourgouin, C, Langel, U, Faye, I, Otvos, L, Wade, JD, Coulibaly, MB, Traore, SF, Tripet, F, Eggleston, P, and Hurd, H

Abstract

A new generation of strategies is evolving that aim to block malaria transmission by employing genetically modified vectors or mosquito pathogens or symbionts that express anti-parasite molecules. Whilst transgenic technologies have advanced rapidly, there is still a paucity of effector molecules with potent anti-malaria activity whose expression does not cause detrimental effects on mosquito fitness. Our objective was to examine a wide range of antimicrobial peptides (AMPs) for their toxic effects on Plasmodium and anopheline mosquitoes. Specifically targeting early sporogonic stages, we initially screened AMPs for toxicity against a mosquito cell line and P. berghei ookinetes. Promising candidate AMPs were fed to mosquitoes to monitor adverse fitness effects, and their efficacy in blocking rodent malaria infection in Anopheles stephensi was assessed. This was followed by tests to determine their activity against P. falciparum in An. gambiae, initially using laboratory cultures to infect mosquitoes, then culminating in preliminary assays in the field using gametocytes and mosquitoes collected from the same area in Mali, West Africa. From a range of 33 molecules, six AMPs able to block Plasmodium development were identified: Anoplin, Duramycin, Mastoparan X, Melittin, TP10 and Vida3. With the exception of Anoplin and Mastoparan X, these AMPs were also toxic to an An. gambiae cell line at a concentration of 25 µM. However, when tested in mosquito blood feeds, they did not reduce mosquito longevity or egg production at concentrations of 50 µM. Peptides effective against cultured ookinetes were less effective when tested in vivo and differences in efficacy against P. berghei and P. falciparum were seen. From the range of molecules tested, the majority of effective AMPs were derived from bee/wasp venoms.

Published
2013

29. Anopheles plumbeus (Diptera: Culicidae) in Europe: a mere nuisance mosquito or potential malaria vector?

Author

Schaffner, Francis; https://orcid.org/0000-0001-9166-7617, Thiéry, I, Kaufmann, C, Zettor, A, Lengeler, C, Mathis, Alexander; https://orcid.org/0000-0002-5499-531X, Bourgouin, C, Schaffner, Francis; https://orcid.org/0000-0001-9166-7617, Thiéry, I, Kaufmann, C, Zettor, A, Lengeler, C, Mathis, Alexander; https://orcid.org/0000-0002-5499-531X, and Bourgouin, C

Abstract

BACKGROUND: Anopheles plumbeus has been recognized as a minor vector for human malaria in Europe since the beginning of the 20th century. In recent years this tree hole breeding mosquito species appears to have exploited novel breeding sites, including large and organically rich man-made containers, with consequently larger mosquito populations in close vicinity to humans. This lead to investigate whether current populations of An. plumbeus would be able to efficiently transmit Plasmodium falciparum, the parasite responsible for the most deadly form of malaria. METHODS: Anopheles plumbeus immatures were collected from a liquid manure pit in Switzerland and transferred as adults to the CEPIA (Institut Pasteur, France) where they were fed on P. falciparum gametocytes produced in vitro. Anopheles gambiae mosquitoes served as controls. Development of P. falciparum in both mosquito species was followed by microscopical detection of oocysts on mosquito midguts and by sporozoite detection in the head/thorax by PCR and microscopy. RESULTS: A total of 293 wild An. plumbeus females from four independent collections successfully fed through a membrane on blood containing P. falciparum gametocytes. Oocysts were observed in mosquito midguts and P. falciparum DNA was detected in head-thorax samples in all four experiments, demonstrating, on a large mosquito sample, that An. plumbeus is indeed receptive to P. falciparum NF54 and able to produce sporozoites. Importantly, the proportion of sporozoites-infected An. plumbeus was almost similar to that of An. gambiae (31 to 88% An. plumbeus versus 67 to 97% An. gambiae). However, the number of sporozoites produced was significantly lower in infected An. plumbeus. CONCLUSION: The results show that a sample of field-caught An. plumbeus has a moderate to high receptivity towards P. falciparum. Considering the increased mobility of humans between Europe and malaria endemic countries and changes in environment and climate, these data strong

Published
2012

30. Killer Bee Molecules: Antimicrobial Peptides as Effector Molecules to Target Sporogonic Stages of Plasmodium

Author

Carter, Victoria, primary, Underhill, Ann, additional, Baber, Ibrahima, additional, Sylla, Lakamy, additional, Baby, Mounirou, additional, Larget-Thiery, Isabelle, additional, Zettor, Agnès, additional, Bourgouin, Catherine, additional, Langel, Ülo, additional, Faye, Ingrid, additional, Otvos, Laszlo, additional, Wade, John D., additional, Coulibaly, Mamadou B., additional, Traore, Sekou F., additional, Tripet, Frederic, additional, Eggleston, Paul, additional, and Hurd, Hilary, additional

Published
2013
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31. Diverged Alleles of the Anopheles gambiae Leucine-Rich Repeat Gene APL1A Display Distinct Protective Profiles against Plasmodium falciparum

Author

Holm, Inge, primary, Lavazec, Catherine, additional, Garnier, Thierry, additional, Mitri, Christian, additional, Riehle, Michelle M., additional, Bischoff, Emmanuel, additional, Brito-Fravallo, Emma, additional, Takashima, Eizo, additional, Thiery, Isabelle, additional, Zettor, Agnes, additional, Petres, Stephane, additional, Bourgouin, Catherine, additional, Vernick, Kenneth D., additional, and Eiglmeier, Karin, additional

Published
2012
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32. In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo

Author

Briolant, Sébastien, primary, Pelleau, Stéphane, additional, Bogreau, Hervé, additional, Hovette, Philippe, additional, Zettor, Agnès, additional, Castello, Jacky, additional, Baret, Eric, additional, Amalvict, Rémy, additional, Rogier, Christophe, additional, and Pradines, Bruno, additional

Published
2011
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36. Killer Bee Molecules: Antimicrobial Peptides as Effector Molecules to Target Sporogonic Stages of Plasmodium.

Author

Carter, Victoria, Underhill, Ann, Baber, Ibrahima, Sylla, Lakamy, Baby, Mounirou, Larget-Thiery, Isabelle, Zettor, Agnès, Bourgouin, Catherine, Langel, Ülo, Faye, Ingrid, Otvos, Laszlo, Wade, John D., Coulibaly, Mamadou B., Traore, Sekou F., Tripet, Frederic, Eggleston, Paul, and Hurd, Hilary

Subjects
AFRICANIZED honeybee, HONEYBEES, ANTIMICROBIAL peptides, ANTIBIOTICS, PLASMODIUM
Abstract

A new generation of strategies is evolving that aim to block malaria transmission by employing genetically modified vectors or mosquito pathogens or symbionts that express anti-parasite molecules. Whilst transgenic technologies have advanced rapidly, there is still a paucity of effector molecules with potent anti-malaria activity whose expression does not cause detrimental effects on mosquito fitness. Our objective was to examine a wide range of antimicrobial peptides (AMPs) for their toxic effects on Plasmodium and anopheline mosquitoes. Specifically targeting early sporogonic stages, we initially screened AMPs for toxicity against a mosquito cell line and P. berghei ookinetes. Promising candidate AMPs were fed to mosquitoes to monitor adverse fitness effects, and their efficacy in blocking rodent malaria infection in Anopheles stephensi was assessed. This was followed by tests to determine their activity against P. falciparum in An. gambiae, initially using laboratory cultures to infect mosquitoes, then culminating in preliminary assays in the field using gametocytes and mosquitoes collected from the same area in Mali, West Africa. From a range of 33 molecules, six AMPs able to block Plasmodium development were identified: Anoplin, Duramycin, Mastoparan X, Melittin, TP10 and Vida3. With the exception of Anoplin and Mastoparan X, these AMPs were also toxic to an An. gambiae cell line at a concentration of 25 µM. However, when tested in mosquito blood feeds, they did not reduce mosquito longevity or egg production at concentrations of 50 µM. Peptides effective against cultured ookinetes were less effective when tested in vivo and differences in efficacy against P. berghei and P. falciparum were seen. From the range of molecules tested, the majority of effective AMPs were derived from bee/wasp venoms. [ABSTRACT FROM AUTHOR]

Published
2013
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37. In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo.

Author

Briolant, Sébastien, Pelleau, Stéphane, Bogreau, Hervé, Hovette, Philippe, Zettor, Agnès, Castello, Jacky, Baret, Eric, Amalvict, Rémy, Rogier, Christophe, and Pradines, Bruno

Subjects
DRUG resistance in microorganisms, PLASMODIUM falciparum, MALARIA, QUININE, MICROBIAL genetics
Abstract

Background: Quinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases. Investigations into the genetic basis for quinine resistance (QNR) suggest that QNR is complex and involves several genes, with either an additive or a pairwise effect. The results obtained when assessing one of these genes, the plasmodial Na+/H+ exchanger, Pfnhe-1, were found to depend upon the geographic origin of the parasite strain. Most of the associations identified have been made in Asian strains; in contrast, in African strains, the influence of Pfnhe on QNR is not apparent. However, a recent study carried out in Kenya did show a significant association between a Pfnhe polymorphism and QNR. As genetic differences may exist across the African continent, more field data are needed to determine if this association exists in other African regions. In the present study, association between Pfnhe and QNR is investigated in a series of isolates from central Africa. Methods: The sequence analysis of the polymorphisms at the Pfnhe-1 ms4760 microsatellite and the evaluation of in vitro quinine susceptibility (by isotopic assay) were conducted in 74 P. falciparum isolates from the Republic of Congo. Results: Polymorphisms in the number of DNNND or NHNDNHNNDDD repeats in the Pfnhe-1 ms4760 microsatellite were not associated with quinine susceptibility. Conclusions: The polymorphism in the microsatellite ms4760 in Pfnhe-1 that cannot be used to monitor quinine response in the regions of the Republic of Congo, where the isolates came from. This finding suggests that there exists a genetic background associated with geographic area for the association that will prevent the use of Pfnhe as a molecular marker for QNR. The contribution of Pfnhe to the in vitro response to quinine remains to be assessed in other regions, including in countries with different levels of drug pressure. [ABSTRACT FROM AUTHOR]

Published
2011
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38. Plasmodium falciparum Na+/H+ Exchanger 1 Transporter Is Involved in Reduced Susceptibility to Quinine

Author

Henry, Maud, Briolant, Sébastien, Zettor, Agnès, Pelleau, Stéphane, Baragatti, Meili, Baret, Eric, Mosnier, Joel, Amalvict, Rémy, Fusai, Thierry, Rogier, Christophe, and Pradines, Bruno

Abstract

Polymorphisms in the Plasmodium falciparum crt (Pfcrt), Pfmdr1, and Pfmrp genes were not significantly associated with quinine (QN) 50% inhibitory concentrations (IC50s) in 23 strains of Plasmodium falciparum. An increased number of DNNND repeats in Pfnhe-1 microsatellite ms4760 was associated with an increased IC50of QN (P = 0.0007). Strains with only one DNNND repeat were more susceptible to QN (mean IC50of 154 nM). Strains with two DNNND repeats had intermediate susceptibility to QN (mean IC50of 548 nM). Strains with three DNNND repeats had reduced susceptibility to QN (mean IC50of 764 nM). Increased numbers of NHNDNHNNDDD repeats were associated with a decreased IC50of QN (P = 0.0020). Strains with profile 7 for Pfnhe-1 ms4760 (ms4760-7) were significantly associated with reduced QN susceptibility (mean IC50of 764 nM). The determination of DNNND and NHNDNHNNDDD repeats in Pfnhe-1 ms4760 could be a good marker of QN resistance and provide an attractive surveillance method to monitor temporal trends in P. falciparum susceptibility to QN. The validity of the markers should be further supported by analyzing more isolates.

Published
2009

39. Plasmodium falciparumNa+/H+Exchanger 1 Transporter Is Involved in Reduced Susceptibility to Quinine

Author

Henry, Maud, Briolant, Sébastien, Zettor, Agnès, Pelleau, Stéphane, Baragatti, Meili, Baret, Eric, Mosnier, Joel, Amalvict, Rémy, Fusai, Thierry, Rogier, Christophe, and Pradines, Bruno

Abstract

ABSTRACTPolymorphisms in the Plasmodium falciparum crt(Pfcrt), Pfmdr1, and Pfmrpgenes were not significantly associated with quinine (QN) 50% inhibitory concentrations (IC50s) in 23 strains of Plasmodium falciparum. An increased number of DNNND repeats in Pfnhe-1microsatellite ms4760 was associated with an increased IC50of QN (P= 0.0007). Strains with only one DNNND repeat were more susceptible to QN (mean IC50of 154 nM). Strains with two DNNND repeats had intermediate susceptibility to QN (mean IC50of 548 nM). Strains with three DNNND repeats had reduced susceptibility to QN (mean IC50of 764 nM). Increased numbers of NHNDNHNNDDD repeats were associated with a decreased IC50of QN (P= 0.0020). Strains with profile 7 for Pfnhe-1ms4760 (ms4760-7) were significantly associated with reduced QN susceptibility (mean IC50of 764 nM). The determination of DNNND and NHNDNHNNDDD repeats in Pfnhe-1ms4760 could be a good marker of QN resistance and provide an attractive surveillance method to monitor temporal trends in P. falciparumsusceptibility to QN. The validity of the markers should be further supported by analyzing more isolates.

Published
2009
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40. DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites

Author

Salah Mecheri, Benoit Witkowski, Flore Nardella, Artur Scherf, Elie Hammam, Ludovic Halby, Roger Peronet, Didier Menard, Véronique Cadet-Daniel, Diane Erdmann, Paola B. Arimondo, Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ED 515 - Complexité du vivant, Sorbonne Université (SU), Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was supported by a European Research Council Advanced Grant (PlasmoSilencing 670301), a Fondation Pasteur Swiss grant and the French Parasitology consortium ParaFrap (ANR-11-LABX0024) to A.S., as well as DARRI Carnot Pasteur MS 2019 Projet INNOV-5-19 to A.S. and P.B.A., DIM1 Health Ile de France 2019 to P.B.A., and PTR Institut Pasteur 2019 (TaME) to L.H. and F.N, We thank Dr. T. Ishino (Department of Medical Zoology, Mie University School of Medicine, Edobashi, Tsu, Japan) for her kind gift of the P. berghei ANKA GFP-expressing strain.(26) We thank Agnès Zettor and Fabrice Agou of the PF-CCB (Institut Pasteur) for the solubility analysis and Eric Legrand (Biology of Host-Parasite Interactions, Institut Pasteur, Paris) for his technical assistance., ANR-11-LABX-0024/11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), European Project: 670301,H2020,ERC-2014-ADG,PlasmoSilencing(2015), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Complexité du Vivant (ED515), Université Paris Cité (UPCité), Réseau International des Instituts Pasteur (RIIP), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), MECHERI, Salah, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, Exoribonuclease-mediated degradation of nascent RNA in Malaria Parasites: A Novel Mechanism in Virulence Gene Silencing - PlasmoSilencing - - H20202015-11-01 - 2020-10-31 - 670301 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Université de Paris (UP)

Subjects
Artemisinins, General Chemical Engineering, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Plasmodium, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, In vivo, parasitic diseases, medicine, [CHIM]Chemical Sciences, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Artemisinin, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, QD1-999, biology, 010405 organic chemistry, Plasmodium falciparum, General Chemistry, medicine.disease, biology.organism_classification, Virology, 0104 chemical sciences, 3. Good health, Chemistry, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Parasitic disease, DNA methylation, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Malaria, Research Article, medicine.drug
Abstract

Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in South-East Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites. Based on a previous report showing the presence of DNA methylation in Plasmodium, we generated new types of DNA methylation inhibitors against malaria parasites. The quinoline–quinazoline-based inhibitors kill parasites, including artemisinin-resistant field isolates adapted to culture, in the low nanomolar range. The compounds target all stages of the asexual cycle, including early rings, during a 6 h treatment period; they reduce DNA methylation in the parasite and show in vivo activity at 10 mg/kg. These potent inhibitors are a new starting point to develop fast-acting antimalarials that could be used in combination with artemisinins., Bisubstrate inhibitors of DNA methylation efficiently kill malaria parasites, including artemisinin-resistant ones. They act in 6 h during all stages of the asexual cycle and show in vivo activity.

Published
2019
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41. Plasmodium falciparum Na+/H+ exchanger 1 transporter is involved in reduced susceptibility to quinine.

Author

Henry M, Briolant S, Zettor A, Pelleau S, Baragatti M, Baret E, Mosnier J, Amalvict R, Fusai T, Rogier C, and Pradines B

Subjects
Animals, Humans, Malaria, Falciparum parasitology, Parasitic Sensitivity Tests, Plasmodium falciparum genetics, Plasmodium falciparum metabolism, Protozoan Proteins chemistry, Protozoan Proteins genetics, Sodium-Hydrogen Exchangers chemistry, Antimalarials pharmacology, Drug Resistance genetics, Microsatellite Repeats genetics, Plasmodium falciparum drug effects, Polymorphism, Genetic, Quinine pharmacology, Sodium-Hydrogen Exchangers genetics
Abstract

Polymorphisms in the Plasmodium falciparum crt (Pfcrt), Pfmdr1, and Pfmrp genes were not significantly associated with quinine (QN) 50% inhibitory concentrations (IC(50)s) in 23 strains of Plasmodium falciparum. An increased number of DNNND repeats in Pfnhe-1 microsatellite ms4760 was associated with an increased IC(50) of QN (P = 0.0007). Strains with only one DNNND repeat were more susceptible to QN (mean IC(50) of 154 nM). Strains with two DNNND repeats had intermediate susceptibility to QN (mean IC(50) of 548 nM). Strains with three DNNND repeats had reduced susceptibility to QN (mean IC(50) of 764 nM). Increased numbers of NHNDNHNNDDD repeats were associated with a decreased IC(50) of QN (P = 0.0020). Strains with profile 7 for Pfnhe-1 ms4760 (ms4760-7) were significantly associated with reduced QN susceptibility (mean IC(50) of 764 nM). The determination of DNNND and NHNDNHNNDDD repeats in Pfnhe-1 ms4760 could be a good marker of QN resistance and provide an attractive surveillance method to monitor temporal trends in P. falciparum susceptibility to QN. The validity of the markers should be further supported by analyzing more isolates.

Published
2009
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