Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Publication Date: 2015-06-19
    Description: There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700930/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700930/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baragana, Beatriz -- Hallyburton, Irene -- Lee, Marcus C S -- Norcross, Neil R -- Grimaldi, Raffaella -- Otto, Thomas D -- Proto, William R -- Blagborough, Andrew M -- Meister, Stephan -- Wirjanata, Grennady -- Ruecker, Andrea -- Upton, Leanna M -- Abraham, Tara S -- Almeida, Mariana J -- Pradhan, Anupam -- Porzelle, Achim -- Martinez, Maria Santos -- Bolscher, Judith M -- Woodland, Andrew -- Norval, Suzanne -- Zuccotto, Fabio -- Thomas, John -- Simeons, Frederick -- Stojanovski, Laste -- Osuna-Cabello, Maria -- Brock, Paddy M -- Churcher, Tom S -- Sala, Katarzyna A -- Zakutansky, Sara E -- Jimenez-Diaz, Maria Belen -- Sanz, Laura Maria -- Riley, Jennifer -- Basak, Rajshekhar -- Campbell, Michael -- Avery, Vicky M -- Sauerwein, Robert W -- Dechering, Koen J -- Noviyanti, Rintis -- Campo, Brice -- Frearson, Julie A -- Angulo-Barturen, Inigo -- Ferrer-Bazaga, Santiago -- Gamo, Francisco Javier -- Wyatt, Paul G -- Leroy, Didier -- Siegl, Peter -- Delves, Michael J -- Kyle, Dennis E -- Wittlin, Sergio -- Marfurt, Jutta -- Price, Ric N -- Sinden, Robert E -- Winzeler, Elizabeth A -- Charman, Susan A -- Bebrevska, Lidiya -- Gray, David W -- Campbell, Simon -- Fairlamb, Alan H -- Willis, Paul A -- Rayner, Julian C -- Fidock, David A -- Read, Kevin D -- Gilbert, Ian H -- 079838/Wellcome Trust/United Kingdom -- 091625/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 100476/Wellcome Trust/United Kingdom -- R01 AI090141/AI/NIAID NIH HHS/ -- R01 AI103058/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Jun 18;522(7556):315-20. doi: 10.1038/nature14451.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. ; Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. ; Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Department of Life Sciences, Imperial College, London SW7 2AZ, UK. ; University of California, San Diego, School of Medicine, 9500 Gilman Drive 0760, La Jolla, California 92093, USA. ; Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia. ; Department of Global Health, College of Public Health University of South Florida, 3720 Spectrum Boulevard, Suite 304, Tampa, Florida 33612, USA. ; GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain. ; TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands. ; Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. ; Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University, Queensland 4111, Australia. ; Malaria Pathogenesis Laboratory, Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, 10430 Jakarta, Indonesia. ; Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland. ; Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland. ; 1] Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia [2] Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LJ, UK. ; 1] Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA [2] Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26085270" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antimalarials/administration & dosage/adverse ; effects/pharmacokinetics/*pharmacology ; Drug Discovery ; Female ; Gene Expression Regulation/*drug effects ; Life Cycle Stages/drug effects ; Liver/drug effects/parasitology ; Malaria/drug therapy/*parasitology ; Male ; Models, Molecular ; Peptide Elongation Factor 2/antagonists & inhibitors/metabolism ; Plasmodium/*drug effects/genetics/growth & development/*metabolism ; Plasmodium berghei/drug effects/physiology ; Plasmodium falciparum/drug effects/metabolism ; Plasmodium vivax/drug effects/metabolism ; Protein Biosynthesis/*drug effects ; Quinolines/administration & dosage/chemistry/pharmacokinetics/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    ISSN: 0956-5663
    Keywords: ATP ; Bioluminescence ; flow sensor ; immobilized enzymes ; ischemia ; lactate ; methacrylate ; microdialysis ; nylon
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Electrical Engineering, Measurement and Control Technology , Physics
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    ISSN: 1432-1041
    Keywords: biperiden ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects. After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml·min−1·kg−1 and 24 l·kg−1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism. Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    ISSN: 1432-1041
    Keywords: phenobarbital ; propylhexedrine salt ; barbexaclone ; bioavailability ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of phenobarbital (PB) was compared after oral administration of equivalent doses of the drug as the acid or the propylhexedrine salt (barbexaclone) to 7 normal volunteers. The absorption and elimination parameters were very similar. It was concluded that propylhexedrine did not affect the serum kinetics of PB given as barbexaclone.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    ISSN: 1432-1041
    Keywords: rifampicin ; rifabutin ; microsomal enzyme induction ; healthy volunteers ; antimicrobial agent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The comparative enzyme inducing effects of rifabutin and the chemically related drug rifampicin have been investigated in 8 normal subjects. Rifampicin 600 mg daily for 7 days caused considerable shortening of the antipyrine half-life and a marked increase in antipyrine clearance, associated with an increased rate of conversion to norantipyrine and, to a lesser extent, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine. The urinary excretion of 6-β-hydroxycortisol was also markedly increased, while plasma GGT activity showed only a slight albeit statistically significant elevation. In the same subjects, rifabutin in the proposed therapeutic dosage (300 mg daily) for 7 days also enhanced the metabolic elimination of antipyrine, with preferential stimulation of the demethylation pathway, and increased the excretion of 6-β-hydroxycortisol, but the magnitude of the effects was signifiantly less than after rifampicin. No significant change in plasma GGT was seen. The results indicate that, contrary to the findings in animals, rifabutin does have enzyme inducing properties in man, although at the dosages assessed they were considerably less than those of rifampicin.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    ISSN: 1432-1106
    Keywords: Peptides ; Glial fibrillary acidic protein ; 4 vessel occlusion model of ischemia ; Immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of transient (30') forebrain ischemia (4 vessel occlusion model) on peptidergic neurons and astroglial cells in various diencephalic and telencephalic areas have been analyzed. The study was performed at various time intervals of reperfusion, i.e. 4 h, 1, 7 and 40 days. Neuropeptide Y (NPY), somatostatin (SRIF), cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP) and arginin-vasopressin (AVP) immunoreactive (IR) neuronal systems and glial fibrillary acidic protein (GFAP)-IR glial cells have been visualized by means of the indirect immunoperoxidase procedure using the avidin-biotin technique. The analysis was performed by means of computer assisted microdensitometry and manual cell counting. At the hippocampal level a huge reduction of neuropeptide (CCK, SRIF, VIP) IR cell bodies was observed, still present 40 days after reperfusion. On the contrary, in the frontoparietal cortex the number of the neuropeptide (CCK, SRIF, VIP, NPY) IR neurons showed a decrease at 4 h, 1 and 7 days after reperfusion followed by a complete recovery at 40 days. A rapid reduction followed by an almost complete recovery (7 days after reperfusion) was also observed at striatal level where SRIF- and NPY-IR neurons were detected. A marked decrease of NPY-IR terminals was observed in the paraventricular and periventricular hypothalamic nuclei and in the paraventricular thalamic nucleus. AVP-IR was markedly reduced in the magnocellular part of the paraventricular nucleus throughout the analyzed period (7 days after reperfusion). GFAP-IR was increased in the hippocampal formation and neostriatum while a not consistent increase was observed at neocortical level. These data point to a differential recovery of peptide-IR and to a different astroglial response in the various brain areas after transient forebrain ischemia. Region-specific factors rather than factors related to neuronal chemical coding seems to play a major role in determining the vulnerability of neuronal populations to transient ischemia.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    ISSN: 0022-0728
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    ISSN: 0022-2828
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    ISSN: 0022-2828
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...