Thousands of chemical starting points for antimalarial lead identification

  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},
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… 

Identification of host interactions for phenotypic antimalarial hits

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

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

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.

New structural classes of antimalarials

Identification of a new chemical class of antimalarials.

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.

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

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
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

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

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.



Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum

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.

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

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.

Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique

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

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

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

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.