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… 
View on Nature
dbbs.wustl.edu
866 Citations
Highly Influential Citations
42
Background Citations
216
Methods Citations
56
Results Citations
6

866 Citations

Identification of host interactions for phenotypic antimalarial hits
TLDR
Results showed that a substantial part of the Malaria Box exhibits the potential of interacting with human GPCRs, which was unexpected beforehand since the pathogenic agent does not contain any GPCR.
Cyclopropyl Carboxamides, a Chemically Novel Class of Antimalarial Agents Identified in a Phenotypic Screen
TLDR
The biological characterization of this chemical family with the generic name cyclopropyl carboxamides is described, showing that inhibition of their still unknown target has very favorable pharmacological consequences but the compounds themselves seem to select for resistance at a high frequency.
Antimalarial drugs: A treasure trove of potential antimalarials
TLDR
Two papers in Nature open up the door to a wealth of compounds that can be explored in the development of novel antimalarials against Plasmodium falciparum, the parasite species that causes the most deaths.
Identification of a new chemical class of antimalarials.
TLDR
This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC(50) values in the low single-digit nanomolar range.
Target identification and validation of novel antimalarials.
TLDR
Methodologies to assist in the determination of a compound's mode of action are reviewed, likely to reveal new targets of novel antimalarial scaffolds usually lacking cross-resistance with known drugs.
Drug discovery: Priming the antimalarial pipeline
TLDR
Two reports raise hopes that alternatives to artemisinins might be found, by identifying thousands of compounds inhibiting the growth of P. falciparum asexual-stage parasites in red blood cells, many distinct in structure and mechanism from current drugs.
Proteases as antimalarial targets: strategies for genetic, chemical, and therapeutic validation
  • Edgar Deu
  • Biology, Chemistry
    The FEBS journal
  • 2017
TLDR
This review presents the current understanding of the biological role proteases play in the malaria parasite life cycle and discusses how the recent advances in Plasmodium genetics, the improvement of protease‐oriented chemical biology approaches, and the development of malaria‐focused pharmacological assays can be combined to achieve a robust biological, chemical and therapeutic validation of Plas modium proteases as viable drug targets.
A New Set of Chemical Starting Points with Plasmodium falciparum Transmission-Blocking Potential for Antimalarial Drug Discovery
TLDR
Screening results for the Tres Cantos Antimalarial Set (TCAMS) report the identification of 98 selective molecules with dual activity against gametocytes and asexual stages, and new chemical structures not connected to previously described antimalarials have been identified.
The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957
TLDR
The antimalarial properties of DDD01034957 are detailed—a novel Antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3.
Medicinal chemistry progression of antimalarial hits from phenotypic whole cell screening of SoftFocus libraries
...
...

References

SHOWING 1-10 OF 48 REFERENCES
In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes.
Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum
TLDR
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.
TLDR
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
TLDR
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.
The effects of anti-bacterials on the malaria parasite Plasmodium falciparum.
Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique
TLDR
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
TLDR
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
TLDR
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
TLDR
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.
...
...