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NIH, Columbia Team Employs Drug and Gene Screens to Find Antimalarial Candidates

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Using genome-wide association and linkage analyses combined with high-throughput growth inhibition assays, researchers from the National Institutes of Health and Columbia University have identified dozens of compounds that appear to thwart various strains of Plasmodium falciparum — along with genetic loci contributing to varying treatment response in the malaria-causing parasite.

The team screened more than 2,800 compounds in 61 malaria parasite lines, identifying 32 compounds that were active against the majority of the parasite lines tested. They also tracked down genetic loci linked to so-called differential chemical phenotypes — differences in how various P. falciparum strains react to various concentrations of a given compound — along with a trio of genes that influenced treatment response in most P. falciparum lines.

"Our analyses show that the majority of differential sensitivity of current P. falciparum populations to many compounds is linked to mutations in pfdhfr, pfmdr1, or pfcrt," co-corresponding author Xin-zhuan Su, a malaria researcher with the National Institute of Allergy and Infectious Diseases, and co-authors wrote, "which suggests that the number of parasite genes that contribute to drug responses may be limited."

The researchers shared their findings in an online paper in Science today.

Therapies based on the anti-malarial drug artemisinin alone or in combination with other drugs are often used to successfully treat malaria cases caused by P. falciparum, the study authors explained. Even so, they noted that new strategies are needed to combat emerging artemisinin resistance and to come up with appropriate companion drugs to use in artemisinin-based combination therapies.

"Unfortunately, parasites resistant to [artemisinin] and its current partner drugs have been reported," the researchers explained. "Combinations of new or existing drugs that are synergistic or act on variant forms of parasite targets may mitigate the emergence of drug resistance."

To look for promising new drug candidates, the team did quantitative, high-throughput screening using a parasite growth inhibition assay.

By looking at how 2,816 compounds from the NIH Chemical Genomics Center's Pharmaceutical Collection, which applied at multiple concentrations, affected the growth of 61 P. falciparum lines, the researchers found 32 compounds with pronounced activity against 45 or more of the parasite lines tested. Seven of the compounds appeared to thwart P. falciparum at lower concentrations than artemisinin.

The researchers also found thousands of so-called "differential chemical phenotypes" that indicated varying P. falciparum responses to compounds depending on the strain tested.

Through a GWAS of 3,354 SNPs combined with follow-up linkage analyses, the researchers were able to narrow in on genetic loci associated with such drug response differences. In particular, they found that three genes — pfcrt, pfmdr1, and pfdhfr —contributed to most of the differential drug responses detected.

Because all of the compounds tested have already been approved for use in humans or other animals, the researchers noted, it may be possible to fast-track the development of treatments based on some of the compounds, either alone or in combination.

"As most of these compounds have been approved for human use, their ability to inhibit parasite growth at nanomolar levels makes them promising candidates for developing new anti-malarial drugs or drug combinations," they explained.

Indeed, the team looked at some of these drug combinations in their follow-up experiments. Through pairwise comparisons using nearly 500 compounds, they were able to scrutinize ways in which compound combinations affected malaria parasite growth and compare them to artemisinin and other existing anti-malarial drugs.

And by organizing compounds based on their activity, the team got new clues about which compounds act on P. falciparum through similar pathways and which may hold the most promise for use in combination therapies.

"By employing genome-wide association and linkage analyses [the study authors] identified candidate compounds with either complementary or distinct drug response signatures, meaning that the compounds act on either the same or different genes or biochemical pathways," Nick Cammack, head of GlaxoSmithKline's Medicines Development Campus for Diseases of the Developing World, wrote in a perspectives article in the same issue of Science.

"This is important," he added, "because using two drugs that target different mechanisms makes it less likely that the parasite will be able to evolve resistance to both drugs."

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