89 results found
Baragaña B, Forte B, Choi R, et al., 2019, Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis., Proc Natl Acad Sci U S A, Vol: 116, Pages: 7015-7020
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.
Yahiya S, Rueda-Zubiaurre A, Delves MJ, et al., 2019, The antimalarial screening landscape-looking beyond the asexual blood stage., Curr Opin Chem Biol, Vol: 50, Pages: 1-9
In recent years, the research agenda to tackle global morbidity and mortality from malaria disease has shifted towards innovation, in the hope that efforts at the frontiers of scientific research may re-invigorate gains made towards eradication. Discovery of new antimalarial drugs with novel chemotypes or modes of action lie at the heart of these efforts. There is a particular interest in drug candidates that target stages of the malaria parasite lifecycle beyond the symptomatic asexual blood stages. This is especially important given the spectre of emerging drug resistance to all current frontline antimalarials. One approach gaining increased interest is the potential of designing novel drugs that target parasite passage from infected individual to feeding mosquito and back again. Action of such therapeutics is geared much more at the population level rather than just concerned with the infected individual. The search for novel drugs active against these stages has been helped by improvements to in vitro culture of transmission and pre-erythrocytic parasite lifecycle stages, robotic automation and high content imaging, methodologies that permit the high-throughput screening (HTS) of compound libraries for drug discovery. Here, we review recent advances in the antimalarial screening landscape, focussed on transmission blocking as a key aim for drug-treatment campaigns of the future.
Malpartida-Cardenas K, Rodriguez-Manzano J, Yu L-S, et al., 2018, Allele-Specific Isothermal Amplification Method Using Unmodified Self-Stabilizing Competitive Primers, ANALYTICAL CHEMISTRY, Vol: 90, Pages: 11972-11980, ISSN: 0003-2700
Fang H, Gomes AR, Klages N, et al., 2018, Epistasis studies reveal redundancy among calcium-dependent protein kinases in motility and invasion of malaria parasites, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
Delves MJ, Miguel-Blanco C, Matthews H, et al., 2018, A high throughput screen for next-generation leads targeting malaria parasite transmission, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
Witmer K, Sherrard-Smith E, Straschil U, et al., 2018, An inexpensive open source 3D-printed membrane feeder for human malaria transmission studies, MALARIA JOURNAL, Vol: 17, ISSN: 1475-2875
Lythl O, Vizcay-Barrena G, Wright KE, et al., 2018, Cellular dissection of malaria parasite invasion of human erythrocytes using viable Plasmodium knowlesi merozoites, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
Lubin AS, Rueda-Zubiaurre A, Matthews H, et al., 2018, Development of a Photo-Cross-Linkable Diaminoquinazoline Inhibitor for Target Identification in Plasmodium falciparum, ACS INFECTIOUS DISEASES, Vol: 4, Pages: 523-530, ISSN: 2373-8227
Baumann H, Matthews H, Li M, et al., 2018, A high-throughput in vitro translation screen towards discovery of novel antimalarial protein translation inhibitors, Publisher: BioRxiv
Drugs that target protein synthesis are well-validated for use as antimicrobials, yet specific high throughput (HTP) methods to screen for those targeting malaria are lacking. Here, we have developed a cell free in vitro translation (IVT) assay for the human malaria parasite, Plasmodium falciparum, which reconstitutes the native parasite protein translation machinery. Combining clarified IVT lysate with a click beetle luciferase reporter gene fused to untranslated regions of Pf histidine-rich proteins (hrp)-2 and 3, the HTP IVT assay accurately reports protein translation in a 384-well plate format using a standard spectrofluorometer. We validate the assay as effective in detecting compounds targeting the ribosome, ribosome co-factors (elongation factor 2) and cytosolic tRNA synthetases as well as its ability to find translation inhibitors in a blind screen using a high-density assay format amenable for high throughput. This demonstrates an ability to reconstitute the breadth of the parasite eukaryotic protein translation machinery in vitro and use it as a powerful platform for antimalarial drug discovery.
Bookwalter CS, Tay CL, McCrorie R, et al., 2017, Reconstitution of the core of the malaria parasite glideosome with recombinant Plasmodium class XIV myosin A and Plasmodium actin, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 292, Pages: 19290-19303, ISSN: 0021-9258
Venkatraman N, Bowyer G, Edwards NJ, et al., 2017, HIGH LEVEL EFFICACY IN HUMANS OF A NEXT-GENERATION PLASMODIUM FALCIPARUM ANTI-SPOROZOITE VACCINE: R21 IN MATRIX-M (TM) ADJUVANT, 66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 594-594, ISSN: 0002-9637
Delves M, Marques S, Ruecker A, et al., 2017, Failure of in vitro differentiation of Plasmodium falciparum gametocytes into ookinetes arises because of poor gamete fertilisation, BioRxiv
A critical step towards malaria elimination will be the interruption of Plasmodium transmission from the human host to the mosquito. At the core of the transmission cycle lies Plasmodium sexual reproduction leading to zygote formation and mosquito midgut colonisation by ookinetes. Whilst in vitro ookinete culture from the murine and avian malaria parasites, Plasmodium berghei and P. gallinaceum, has greatly increased our knowledge of transmission biology; efforts to mimic the process in the human parasite P. falciparum have, to date, had only limited success. Using fluorescence microscopy and flow cytometry with antibodies specific to the male gametocyte and developing ookinetes, we sought to evaluate P. falciparum ookinete production using previously published in vitro protocols. We then compared in vitro versus in vivo ookinete production in both P. falciparum and P. berghei parasites, exploring potential barriers to complete development. Finally, we sought to test a wide range of literature-led culture conditions towards further optimisation of in vitro P. falciparum ookinete production. Despite extensive testing, our efforts to replicate published methods did not produce appreciable quantities of fully formed P. falciparum ookinetes in vitro. In parallel, however, gametocyte cultures that failed to differentiate fully in vitro successfully developed into ookinetes in vivo with an efficiency approximating that of P. berghei. Flow cytometry analysis showed that this disparity likely lies with the poor fertilization of P. falciparum gametes in vitro. Attempts to improve gametocyte fertility or define conditions more permissive to fertilisation/ookinete survival in vitro were also unsuccessful. Current in vitro conditions for P. falciparum ookinete production are not optimal for gamete fertilisation either due to the lack of parasite-species-specific mosquito factors missing from in vitro culture, or non-permissive cues contaminating culture preparations.
Miguel-Blanco C, Molina I, Bardera AI, et al., 2017, ACCELERATING THE DISCOVERY OF TRANSMISSION-BLOCKING DRUGS: HT SCREENING WITH A NOVEL PLASMODIUM FALCIPARUM FUNCTIONAL GAMETOCYTE ASSAY, 65th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 82-82, ISSN: 0002-9637
Delves MJ, Miguel-Blanco C, Matthews H, et al., 2017, HIGH THROUGHPUT DISCOVERY OF NEW DRUGS TARGETING MALARIA PARASITE TRANSMISSION - TOWARDS THE ALTRUISTIC ANTIMALARIAL, 66th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 305-305, ISSN: 0002-9637
Wirth DF, Winzeler EA, Fenton B, et al., 2017, malERA: An updated research agenda for basic science and enabling technologies in malaria elimination and eradication, PLOS MEDICINE, Vol: 14, ISSN: 1549-1277
Bargieri DY, Thiberge S, Tay C, et al., 2017, PLASMODIUM MTRAP IS ESSENTIAL FOR GAMETE EGRESS AND PARASITE TRANSMISSION TO MOSQUITOES, 65th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 588-588, ISSN: 0002-9637
Das S, Lemgruber L, Tay CL, et al., 2017, Multiple essential functions of Plasmodium falciparum actin-1 during malaria blood-stage development, BMC BIOLOGY, Vol: 15, ISSN: 1741-7007
Wong W, Bai X-C, Sleebs BE, et al., 2017, Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis, NATURE MICROBIOLOGY, Vol: 2, ISSN: 2058-5276
Miguel-Blanco C, Molina I, Bardera AI, et al., 2017, Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
Koch M, Wright KE, Otto O, et al., 2017, Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 114, Pages: 4225-4230, ISSN: 0027-8424
Baum J, Richard D, Riglar DT, 2017, Malaria parasite invasion: achieving superb resolution., Cell Host and Microbe, Vol: 21, Pages: 294-296, ISSN: 1931-3128
It is only in the last decade that sub-cellular resolution of red cell invasion by the malaria parasite Plasmodium falciparum has been possible. Here we look back on the development of methodologies that led to this possibility and the subsequent advancements made in understanding this key event in malaria disease.
Johnson S, Rahmani R, Drew DR, et al., 2016, Truncated Latrunculins as Actin Inhibitors Targeting Plasmodium falciparum Motility and Host Cell Invasion, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 59, Pages: 10994-11005, ISSN: 0022-2623
Bargieri DY, Thiberge S, Tay CL, et al., 2016, Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes, CELL HOST & MICROBE, Vol: 20, Pages: 618-630, ISSN: 1931-3128
Delves MJ, Straschil U, Ruecker A, et al., 2016, Routine in vitro culture of P. falciparum gametocytes to evaluate novel transmission-blocking interventions, NATURE PROTOCOLS, Vol: 11, Pages: 1668-1680, ISSN: 1754-2189
Tardieux I, Baum J, 2016, Reassessing the mechanics of parasite motility and host-cell invasion, JOURNAL OF CELL BIOLOGY, Vol: 214, Pages: 507-515, ISSN: 0021-9525
Bane KS, Lepper S, Kehrer J, et al., 2016, The Actin Filament-Binding Protein Coronin Regulates Motility in Plasmodium Sporozoites, PLOS PATHOGENS, Vol: 12, ISSN: 1553-7366
Koch M, Baum J, 2016, The mechanics of malaria parasite invasion of the human erythrocyte - towards a reassessment of the host cell contribution, CELLULAR MICROBIOLOGY, Vol: 18, Pages: 319-329, ISSN: 1462-5814
Zuccala ES, Satchwell TJ, Angrisano F, et al., 2016, Quantitative phospho-proteomics reveals the Plasmodium merozoite triggers pre-invasion host kinase modification of the red cell cytoskeleton, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322
Riglar DT, Whitehead L, Cowman AF, et al., 2016, Localisation-based imaging of malarial antigens during erythrocyte entry reaffirms a role for AMA1 but not MTRAP in invasion, JOURNAL OF CELL SCIENCE, Vol: 129, Pages: 228-242, ISSN: 0021-9533
Olshina MA, Baumann H, Willison KR, et al., 2016, Plasmodium actin is incompletely folded by heterologous protein-folding machinery and likely requires the native Plasmodium chaperonin complex to enter a mature functional state, FASEB JOURNAL, Vol: 30, Pages: 405-416, ISSN: 0892-6638
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.