Article
Biology
Marc A. Schureck, Joseph E. Darling, Alan Merk, Jinfeng Shao, Geervani Daggupati, Prakash Srinivasan, Paul Dominic B. Olinares, Michael P. Rout, Brian T. Chait, Kurt Wollenberg, Sriram Subramaniam, Sanjay A. Desai
Summary: Malaria parasites use the RhopH complex for erythrocyte invasion and nutrient uptake, with the complex integrating into the erythrocyte membrane through a PTEX translocon-dependent process after transferring to a new host cell. The complex is tightly assembled with extensive disulfide bonding and predicted transmembrane helices, poised for large-scale rearrangements for host membrane insertion.
Article
Pharmacology & Pharmacy
Thibaud Reyser, Lucie Paloque, Michel Nguyen, Jean-Michel Augereau, Matthew John Fuchter, Marie Lopez, Paola B. Arimondo, Storm Hassell-Hart, John Spencer, Luisa Di Stefano, Francoise Benoit-Vical
Summary: The use of artemisinin and its derivatives has helped reduce malaria burden, but artemisinin-resistant parasites pose a threat to eradication efforts. Drugs targeting epigenetic mechanisms show promise in countering artemisinin resistance by inhibiting parasite recovery after artemisinin exposure.
Article
Biology
Abhinay Ramaprasad, Severina Klaus, Olga Douvropoulou, Richard Culleton, Arnab Pain
Summary: Through extensive genetic and phenotype analysis of P. vinckei, it was found that the five subspecies have diverged widely and undergone large-scale genome rearrangements. Region-specific selection pressures were observed particularly on genes involved in mosquito transmission. The highland forest subspecies P. v. vinckei has a smaller genome and reduced multigene family repertoire, making it suitable for transfection and ideal for reverse genetics research. Amenable to genetic crosses, P. vinckei isolates show a large degree of phenotypic and genotypic diversity. Their inclusion in studies provides new insights into the evolution of RMPs and multigene families, making them valuable resources for research on parasite virulence and immunogenicity.
Article
Multidisciplinary Sciences
Laura E. de Vries, Patrick A. M. Jansen, Catalina Barcelo, Justin Munro, Julie M. J. Verhoef, Charisse Flerida A. Pasaje, Kelly Rubiano, Josefine Striepen, Nada Abla, Luuk Berning, Judith M. Bolscher, Claudia Demarta-Gatsi, Rob W. M. Henderson, Tonnie Huijs, Karin M. J. Koolen, Patrick K. Tumwebaze, Tomas Yeo, Anna C. C. Aguiar, Inigo Angulo-Barturen, Alisje Churchyard, Jake Baum, Benigno Crespo Fernandez, Aline Fuchs, Francisco-Javier Gamo, Rafael V. C. Guido, Maria Belen Jimenez-Diaz, Dhelio B. Pereira, Rosemary Rochford, Camille Roesch, Laura M. Sanz, Graham Trevitt, Benoit Witkowski, Sergio Wittlin, Roland A. Cooper, Philip J. Rosenthal, Robert W. Sauerwein, Joost Schalkwijk, Pedro H. H. Hermkens, Roger Bonnert, Brice Campo, David A. Fidock, Manuel Llinas, Jacquin C. Niles, Taco W. A. Kooij, Koen J. Dechering
Summary: In this study, a pantothenamide, MMV693183, was presented as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor with attractive drug-like properties and in vivo efficacy. The compound showed potent activity against Plasmodium falciparum and Plasmodium vivax, and effectively blocked transmission to Anopheles mosquitoes. These findings make MMV693183 a promising candidate for further clinical development.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Ioanna Deni, Barbara H. Stokes, Kurt E. Ward, Kate J. Fairhurst, Charisse Flerida A. Pasaje, Tomas Yeo, Shirin Akbar, Heekuk Park, Ryan Muir, Daniella S. Bick, Wenhu Zhan, Hao Zhang, Yi Jing Liu, Caroline L. Ng, Laura A. Kirkman, Jehad Almaliti, Alexandra E. Gould, Maelle Duffey, Anthony J. O'Donoghue, Anne-Catrin Uhlemann, Jacquin C. Niles, Paula C. A. da Fonseca, William H. Gerwick, Gang Lin, Matthew Bogyo, David A. Fidock
Summary: This study found that vinyl sulfone inhibitors are effective against artemisinin-resistant parasites and do not readily develop resistance. Additionally, resistance to one inhibitor can increase sensitivity to other types of inhibitors. These findings suggest that dual targeting of different proteasome subunits using covalent inhibitors may be a potential strategy for restoring artemisinin activity and combating drug-resistant malaria spread.
CELL CHEMICAL BIOLOGY
(2023)
Article
Cell Biology
Eva S. Istvan, Francisco Guerra, Matthew Abraham, Kuo-Sen Huang, Frances Rocamora, Haoshuang Zhao, Lan Xu, Charisse Pasaje, Krittikorn Kumpornsin, Madeline R. Luth, Haissi Cui, Tuo Yang, Sara Palomo Diaz, Maria G. Gomez-Lorenzo, Tarrick Qahash, Nimisha Mittal, Sabine Ottilie, Jacquin Niles, Marcus C. S. Lee, Manue Llinas, Nobutaka Kato, John Okombo, David A. Fidock, Paul Schimmel, Francisco Javier Gamo, Daniel E. Goldberg, Elizabeth A. Winzeler
Summary: Development of antimalarial compounds into clinical candidates is costly and difficult without detailed knowledge of the target. Whole-genome sequencing of parasite clones evolved with thienopyrimidine compounds revealed mutations in the P. falciparum cytoplasmic isoleucyl tRNA synthetase (cIRS), which was shown to be a validated target for next-generation malaria medicines. The study also identified a noncompetitive allosteric binding site for P. vivax cIRS, distinct from known cIRS inhibitors.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Review
Parasitology
John Okombo, Mariko Kanai, Ioanna Deni, David A. Fidock
Summary: Recent progress in genomics and molecular genetics has enabled novel approaches to study gene functions in disease-causing pathogens. In the human malaria parasite Plasmodium falciparum, genome-based analyses, site-directed genome editing, and genetic systems have been invaluable in defining antimalarial resistance and accelerating drug discovery efforts. These approaches have contributed to advancing our understanding of Plasmodium biology and characterizing genomic loci associated with antimalarial drug responses.
TRENDS IN PARASITOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Manish Kumar, Kristen Skillman, Manoj T. Duraisingh
Summary: Malaria caused by Plasmodium parasites is a life-threatening infectious disease, and Plasmodium falciparum in particular can sense nutrient levels in the blood-stage to drive changes in gene expression affecting proliferation, antigenic variation, and transmission.
MOLECULAR MICROBIOLOGY
(2021)
Article
Chemistry, Medicinal
Aloysus Lawong, Suraksha Gahalawat, John Okombo, Josefine Striepen, Tomas Yeo, Sachel Mok, Ioanna Deni, Jessica L. Bridgford, Hanspeter Niederstrasser, Anwu Zhou, Bruce Posner, Sergio Wittlin, Francisco Javier Gamo, Benigno Crespo, Alisje Churchyard, Jake Baum, Nimisha Mittal, Elizabeth Winzeler, Benoit Laleu, Michael J. Palmer, Susan A. Charman, David A. Fidock, Joseph M. Ready, Margaret A. Phillips
Summary: A novel tetrazole-based antimalarial series with fast-kill kinetics and low propensity for resistance has been identified. This series targets the heme polymerization pathway and shows a similar mechanism of action to chloroquine, with only modest resistance observed in drug selections. This discovery has the potential to lead to the development of a new and effective malaria treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Jorge Aza-Conde, Cesar Reyes, Carlos F. Suarez, Manuel A. Patarroyo, Manuel E. Patarroyo
Summary: This work presents a methodology for developing a minimal, subunit-based, multi-epitope, multi-stage, chemically synthesized anti-Plasmodium falciparum malaria vaccine. The study selected modified high activity binding peptides from functionally relevant regions for parasite binding to and invasion of red blood cells, which were found to be highly immunogenic and protective immune response inducers. The data obtained suggests that some of these peptides could be excellent components of a fully protective antimalarial vaccine.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Cell Biology
Maximilian Julius Lautenbach, Victor Yman, Carolina Sousa Silva, Nadir Kadri, Ioanna Broumou, Sherwin Chan, Sina Angenendt, Klara Sonden, David Fernando Plaza, Anna Farnert, Christopher Sundling
Summary: This study comprehensively profiles the immune system of patients with acute symptomatic Plasmodium falciparum malaria over a year. The results indicate that a dampened inflammatory response is associated with reduced expansion of gamma delta T cells, early expansion of CD16(+) monocytes, and production of specific antibodies. This control of infection and reduction of inflammation suggest a potential mechanism for the establishment of tolerance following repeated malaria exposure.
Article
Multidisciplinary Sciences
Aissata Barry, John Bradley, Will Stone, Moussa W. Guelbeogo, Kjerstin Lanke, Alphonse Ouedraogo, Issiaka Soulama, Issa Nebie, Samuel S. Serme, Lynn Grignard, Catriona Patterson, Lindsey Wu, Jessica J. Briggs, Owen Janson, Shehu S. Awandu, Mireille Ouedraogo, Casimire W. Tarama, Desire Kargougou, Soumanaba Zongo, Sodiomon B. Sirima, Matthias Marti, Chris Drakeley, Alfred B. Tiono, Teun Bousema
Summary: The study found that in children in Burkina Faso, chronic infections of Plasmodium falciparum have higher gametocyte production and mosquito infectivity. Incident infections typically require treatment before reaching a sufficient density of mature gametocytes to infect mosquitoes.
NATURE COMMUNICATIONS
(2021)
Article
Plant Sciences
Mariscal Brice Tchatat Tali, Boniface Pone Kamdem, Jean Claude Tchouankeu, Fabrice Fekam Boyom
Summary: This study summarizes the latest information on the antimalarial, antileishmanial, and antitrypanosomal activities of plants from the genus Terminalia, as well as their mechanisms of action. Terminalia plant extracts show a wide range of antiparasitic activities against Plasmodium, Leishmania, and Trypanosoma species, but their in vivo effectiveness is not well known. Overall, Terminalia plants have shown potential as candidates for drug development against malaria, leishmaniasis, and trypanosomiasis, but further in vivo experiments and detailed mechanism studies are needed.
SOUTH AFRICAN JOURNAL OF BOTANY
(2023)
Article
Biochemistry & Molecular Biology
James M. Murithi, Ioanna Deni, Charisse Flerida A. Pasaje, John Okombo, Jessica L. Bridgford, Nina F. Gnadig, Rachel L. Edwards, Tomas Yeo, Sachel Mok, Anna Y. Burkhard, Olivia Coburn-Flynn, Eva S. Istvan, Tomoyo Sakata-Kato, Maria G. Gomez-Lorenzo, Annie N. Cowell, Kathryn J. Wicht, Claire Le Manach, Gavreel F. Kalantarov, Sumanta Dey, Maelle Duffey, Benoit Laleu, Amanda K. Lukens, Sabine Ottilie, Manu Vanaerschot, Ilya N. Trakht, Francisco-Javier Gamo, Dyann F. Wirth, Daniel E. Goldberg, Audrey R. Odom John, Kelly Chibale, Elizabeth A. Winzeler, Jacquin C. Niles, David A. Fidock
Summary: This study identifies the transporter ABCI3 and the chloroquine resistance transporter PfCRT as key players in drug resistance in Plasmodium falciparum. The mode of action of the compound imidazopyridine is attributed to inhibition of heme detoxification.
CELL CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Harsha Valluri, Amritansh Bhanot, Shreeya Shah, Navya Bhandaru, Sandeep Sundriyal
Summary: Most antimalarials contain basic N-heterocycles with amine functionalities. However, the role of basic nitrogen (BaN) in antimalarial drug design has not been systematically studied. Cheminformatics analysis shows that BaN is an important feature of antimalarial space and its presence is associated with higher potency. Moreover, the addition of BaN enhances the antiplasmodial activity in different scaffolds.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Margaret Pain, Alexandra W. Fuller, Katherine Basore, Ajay D. Pillai, Tsione Solomon, Abdullah A. B. Bokhari, Sanjay A. Desai
Article
Biology
Daisuke Ito, Marc A. Schureck, Sanjay A. Desai
Article
Cell Biology
Ambuj K. Kushwaha, Liana Apolis, Daisuke Ito, Sanjay A. Desai
CELLULAR MICROBIOLOGY
(2018)
Article
Parasitology
Jose M. Ribeiro, Meera Garriga, Nicole Potchen, Anna K. Crater, Ankit Gupta, Daisuke Ito, Sanjay A. Desai
INTERNATIONAL JOURNAL FOR PARASITOLOGY
(2018)
Article
Biochemistry & Molecular Biology
Yair Fastman, Shany Assaraf, Miriam Rose, Elad Milrot, Katherine Basore, B. Sivanandam Arasu, Sanjay A. Desai, Michael Elbaum, Ron Dzikowski
NUCLEIC ACIDS RESEARCH
(2018)
Article
Microbiology
Ankit Gupta, Praveen Balabaskaran-Nina, Wang Nguitragool, Gagandeep S. Saggu, Marc A. Schureck, Sanjay A. Desai
Article
Biology
Gunjan Arora, Geoffrey T. Hart, Javier Manzella-Lapeira, Justin Y. A. Doritchamou, David L. Narum, L. Michael Thomas, Joseph Brzostowski, Sumati Rajagopalan, Ogobara K. Doumbo, Boubacar Traore, Louis H. Miller, Susan K. Pierce, Patrick E. Duffy, Peter D. Crompton, Sanjay A. Desai, Eric O. Long
Article
Biotechnology & Applied Microbiology
Liana Apolis, Joanna Olivas, Prakash Srinivasan, Ambuj K. Kushwaha, Sanjay A. Desai
Review
Parasitology
Praveen Balabaskaran-Nina, Sanjay A. Desai
PARASITES & VECTORS
(2018)
Article
Microbiology
Ankit Gupta, Abdullah A. B. Bokhari, Ajay D. Pillai, Anna K. Crater, Jeanine Gezelle, Gagandeep Saggu, Armiyaw S. Nasamu, Suresh M. Ganesan, Jacquin C. Niles, Sanjay A. Desai
Article
Microbiology
Moaz Ahmad, Javier Manzella-Lapeira, Gagandeep Saggu, Daisuke Ito, Joseph A. Brzostowski, Sanjay A. Desaia
Review
Parasitology
Sanjay A. Desai
TRENDS IN PARASITOLOGY
(2022)
Article
Microbiology
Jinfeng Shao, Gunjan Arora, Javier Manzella-Lapeira, Joseph A. Brzostowski, Sanjay A. Desai
Summary: This study developed a new method called RISE, which enables continuous nondestructive tracking of antigen exposure on infected cells. Using RISE, researchers tracked the membrane insertion of a parasite antigen called CLAG3 in infected red blood cells. They found that CLAG3 insertion occurs at specific parasite stages and is required for the formation of a nutrient uptake channel. Furthermore, they defined constraints on protein insertion at the host cell membrane by varying the size and charge of the extracellular domain.
Article
Biophysics
Jeremiah N. Sims, EJun Yun, Jonathan Chu, Mansoor A. Siddiqui, Sanjay A. Desai
Summary: In this study, a robust microplate-based assay for erythrocyte Ca++ efflux was developed and optimized, allowing radioisotope-free kinetic measurements of the Ca++ pump and facilitating the screening for specific inhibitors.
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
(2023)
Article
Multidisciplinary Sciences
Mariame A. Sylla, Ankit Gupta, Jinfeng Shao, Sanjay A. Desai
Summary: The human malaria parasite, Plasmodium falciparum, uses the PfATP4 cation pump for ion homeostasis. The expression of the mammalian ion channel TRPV1 at the parasite membrane revealed the role of cation dysregulation and confirmed the impact of PfATP4 inhibitors. Activation of TRPV1 resulted in parasite death and cholesterol redistribution, while low Na+ media accentuated parasite killing. A ligand-resistant mutant with reduced permeability highlighted the mechanism of parasite resistance to antimalarials targeting ion homeostasis.
