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Spiroindolones, a Potent Compound Class for the Treatment of Malaria
The preclinical profile for an optimized spiroindolone drug candidate, NITD609, shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
Targeting Plasmodium PI(4)K to eliminate malaria
It is shown that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate.
Na+ Regulation in the Malaria Parasite Plasmodiumfalciparum Involves the Cation ATPase PfATP4 and Is a Target of the Spiroindolone Antimalarials
Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility.
A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability, and an in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines.
Selective and Specific Inhibition of the Plasmodium falciparum Lysyl-tRNA Synthetase by the Fungal Secondary Metabolite Cladosporin
M1 Protein Allows Group A Streptococcal Survival in Phagocyte Extracellular Traps through Cathelicidin Inhibition
- X. Lauth, M. von Köckritz-Blickwede, V. Nizet
- Biology, MedicineJournal of Innate Immunity
- 20 February 2009
Increased resistance to host cathelicidin and killing within phagocyte extracellular traps contribute to the propensity of M1 GAS strains to produce invasive infections.
Mitotic Evolution of Plasmodium falciparum Shows a Stable Core Genome but Recombination in Antigen Families
This work studied the complete genomes of different Plasmodium falciparum clones that had been propagated asexually over one year in the presence and absence of drug pressure to model the frequency at which drug or immune resistance alleles will emerge under a well-defined set of assumptions.
In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen
- D. Plouffe, A. Brinker, E. Winzeler
- Biology, MedicineProceedings of the National Academy of Sciences
- 1 July 2008
An efficient and robust high-throughput cell-based screen based on proliferation of Plasmodium falciparum in erythrocytes, which identified most known antimalarials and many novel chemical scaffolds, which likely act through both known and novel pathways.
Coiled-Coil Irregularities and Instabilities in Group A Streptococcus M1 Are Required for Virulence
- C. McNamara, A. Zinkernagel, P. Macheboeuf, M. Cunningham, V. Nizet, P. Ghosh
- 7 March 2008
Antigenically variable M proteins are major virulence factors and immunogens of the human pathogen group A Streptococcus (GAS). Here, we report the ∼3 angstrom resolution structure of a GAS M1…
Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design
- Michael B. Harbut, Bhumit A Patel, D. Greenbaum
- BiologyProceedings of the National Academy of Sciences
- 11 December 2012
Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin- and proteasome-mediated process known as ER-associated…