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1.
PLoS One ; 9(2): e87923, 2014.
Article in English | MEDLINE | ID: mdl-24503862

ABSTRACT

Huntington's disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.


Subject(s)
Antibodies, Monoclonal/pharmacology , Huntington Disease/metabolism , Receptor, trkB/agonists , Receptor, trkB/metabolism , Animals , Antibodies, Monoclonal/chemistry , Brain-Derived Neurotrophic Factor/metabolism , Cell Death/drug effects , Cell Line , Cells, Cultured , Corpus Striatum/cytology , Corpus Striatum/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Huntington Disease/drug therapy , Mice, Transgenic , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Rats , Signal Transduction/drug effects
2.
J Med Chem ; 55(22): 10010-21, 2012 Nov 26.
Article in English | MEDLINE | ID: mdl-23043329

ABSTRACT

Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 µg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.


Subject(s)
Anti-Bacterial Agents/pharmacology , Benzoates/pharmacology , Enterococcus/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Nucleoside-Phosphate Kinase/antagonists & inhibitors , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Thymine/analogs & derivatives , Vancomycin Resistance/drug effects , Anti-Bacterial Agents/chemical synthesis , Benzoates/chemical synthesis , Catalytic Domain , Crystallography, X-Ray , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Nucleoside-Phosphate Kinase/metabolism , Structure-Activity Relationship , Thymine/chemical synthesis , Thymine/pharmacology
3.
J Med Chem ; 55(7): 3144-54, 2012 Apr 12.
Article in English | MEDLINE | ID: mdl-22380711

ABSTRACT

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 µM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria.


Subject(s)
Antimalarials/chemistry , Databases, Factual , Plasmodium falciparum/enzymology , Protozoan Proteins/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Quinone Reductases/antagonists & inhibitors , Antimalarials/pharmacology , Bayes Theorem , High-Throughput Screening Assays , Informatics , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Principal Component Analysis , Protozoan Proteins/chemistry , Quinone Reductases/chemistry
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