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Susan A. Charman  - - - 
Top co-authors
Margaret A. Phillips

114 shared publications

Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Harry Hines Blvd, Dallas, TX, United States of America

Martine Keenan

3 shared publications

Epichem Pty Ltd., Murdoch University Campus, South Street, Murdoch, Western Australia 6150, Australia

David M. Shackleford

2 shared publications

Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Parkville, Australia

134
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Publication Record
Distribution of Articles published per year 
(1993 - 2018)
Total number of journals
published in
 
24
 
Publications See all
Article 0 Reads 0 Citations Using Human Plasma as an Assay Medium in Caco-2 Studies Improves Mass Balance for Lipophilic Compounds Kasiram Katneni, Thao Pham, Jessica Saunders, Gong Chen, Rah... Published: 17 September 2018
Pharmaceutical Research, doi: 10.1007/s11095-018-2493-3
DOI See at publisher website ABS Show/hide abstract
To examine the utility of human plasma as an assay medium in Caco-2 permeability studies to overcome poor mass balance and inadequate sink conditions frequently encountered with lipophilic compounds. Caco-2 permeability was assessed for reference compounds with known transport mechanisms using either pH 7.4 buffer or human plasma as the assay medium in both the apical and basolateral chambers. When using plasma, Papp values were corrected for the unbound fraction in the donor chamber. The utility of the approach was assessed by measuring the permeability of selected antimalarial compounds using the two assay media. Caco-2 cell monolayer integrity and P-gp transporter function were unaffected by the presence of human plasma in the donor and acceptor chambers. For many of the reference compounds having good mass balance with buffer as the medium, higher Papp values were observed with plasma, likely due to improved acceptor sink conditions. The lipophilic antimalarial compounds exhibited low mass balance with buffer, however the use of plasma markedly improved mass balance allowing the determination of more reliable Papp values. The results support the utility of human plasma as an alternate Caco-2 assay medium to improve mass balance and permeability measurements for lipophilic compounds.
Article 0 Reads 5 Citations The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Pa... David I. Finkelstein, Jessica L. Billings, Paul A. Adlard, S... Published: 28 June 2017
Acta Neuropathologica Communications, doi: 10.1186/s40478-017-0456-2
DOI See at publisher website PubMed View at PubMed ABS Show/hide abstract
Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD.
Article 0 Reads 6 Citations Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Bin... Geoffrey Schwertz, Matthias C. Witschel, Matthias Rottmann, ... Published: 13 June 2017
Journal of Medicinal Chemistry, doi: 10.1021/acs.jmedchem.7b00008
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Article 0 Reads 12 Citations A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance Paul M. O’Neill, Richard K. Amewu, Susan A. Charman, Sunil S... Published: 24 May 2017
Nature Communications, doi: 10.1038/ncomms15159
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K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
Article 0 Reads 18 Citations Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yass... Published: 26 April 2017
Science Translational Medicine, doi: 10.1126/scitranslmed.aad9735
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Article 0 Reads 5 Citations Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis Anh T. Tran, Emma E. Watson, Venugopal Pujari, Trent Conroy,... Published: 01 March 2017
Nature Communications, doi: 10.1038/ncomms14414
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Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.
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