Thousands of chemical starting points for antimalarial lead identification
@article{Gamo2010ThousandsOC, title={Thousands of chemical starting points for antimalarial lead identification}, author={Francisco Javier Gamo and Laura M Sanz and Jaume Vidal and Cristina de Cozar and Emilio Alvarez and Jos{\'e} Lu{\'i}s Lavandera and Dana E. Vanderwall and Darren V. S. Green and Vinod Kumar and Samiul Hasan and James R. Brown and Catherine E. Peishoff and Lon R. Cardon and Jose F. Garc{\'i}a-Bustos}, journal={Nature}, year={2010}, volume={465}, pages={305-310} }
Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline’s chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 µM…
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References
SHOWING 1-10 OF 48 REFERENCES
In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes.
- MedicineInternational journal for parasitology
- 2008
Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum
- Medicine, BiologyNature
- 2000
Direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine is provided, which has important implications for the development and efficacy of future antimalarial agents.
Data-mining approaches reveal hidden families of proteases in the genome of malaria parasite.
- BiologyGenome research
- 2003
This study identifies 92 putative proteases in the P. falciparum genome that have been implicated to be central mediators for essential parasitic activity and distantly related to the vertebrate host.
Antimalarial drug discovery: efficacy models for compound screening
- Biology, MedicineNature Reviews Drug Discovery
- 2004
Different in vitro and in vivo screens for antimalarial drug discovery are suggested and a streamlined process for evaluating new compounds on the path from drug discovery to development is recommended.
Drugging the Plasmodium kinome: the benefits of academia-industry synergy.
- BiologyTrends in pharmacological sciences
- 2008
The effects of anti-bacterials on the malaria parasite Plasmodium falciparum.
- BiologyMolecular and biochemical parasitology
- 2007
Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique
- Medicine, BiologyAntimicrobial Agents and Chemotherapy
- 1979
A rapid, semiautomated microdilution method was developed for measuring the activity of potential antimalarial drugs against cultured intraerythrocytic asexual forms of the human malaria parasite Plasmodium falciparum, and results demonstrated that the method is sensitive and precise.
Drugs for bad bugs: confronting the challenges of antibacterial discovery
- BiologyNature Reviews Drug Discovery
- 2007
The experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years is shared, and what is learned is looked at and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
Inhibitors of Nonhousekeeping Functions of the Apicoplast Defy Delayed Death in Plasmodium falciparum
- BiologyAntimicrobial Agents and Chemotherapy
- 2006
It is demonstrated that antibiotics like clindamycin, chloramphenicol, and tetracycline, inhibitors of prokaryotic protein synthesis, invoke the delayed death phenotype in Plasmodium falciparum, too, as evident from a specific reduction of apicoplast genome copy number.
Plasmodium falciparum Drug Resistance in Madagascar: Facing the Spread of Unusual pfdhfr and pfmdr-1 Haplotypes and the Decrease of Dihydroartemisinin Susceptibility
- MedicineAntimicrobial Agents and Chemotherapy
- 2009
The first comprehensive spatiotemporal picture of Plasmodium falciparum resistance in various geographic areas in Madagascar showed unusual profiles of chloroquine susceptibility in Madagascar, a rapid rise in the frequency of parasites with both the pfdhfr and the pFDhps mutations and the progressive loss of the most susceptible isolates to artemisinin derivatives.