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Matrix Combination Screening

Development of Novel Chemical Genomic Platforms for Pathogenic Protozoa

Scientific Synopsis

Pathogenic protozoa remain a global burden with an enormous health, social and economic impact. The burden is exacerbated by the lack of licensed vaccines, although developmental efforts are ongoing. Where chemotherapeutics are available, their usefulness is threatened by the emergence and spread of drug-resistant parasites. The requirement for new chemotherapeutic agents necessitates global development efforts.

To facilitate these efforts, NCATS endeavors to develop and validate innovative strategies for the discovery of new antiparasitic agents and gain insight into mechanism of action. For example, NCATS leveraged its high-throughput matrix screening capabilities to assay approximately 14,000 drug combinations against three distinct Plasmodium falciparum strains. NCATS scientists identified novel drug classes, including calcium homeostasis modulators and inhibitors of phosphatidylinositide 3-kinases, that demonstrated significant synergy with currently approved antimalarial drugs.

In collaboration with Dr. Roberto Moraes Barros Ph.D. and Thomas Wellems, M.D., Ph.D., at NIH’s National Institute of Allergy and Infectious Diseases, NCATS is developing a comparative screening platform to assay compound activity against multiple species of Plasmodium infecting humans.

Lead Collaborators

Craig J. Thomas, Ph.D., NCATS, NIH
Richard T. Eastman, Ph.D., NCATS, NIH

Publications

Eastman RT, Khine P, Huang R, Thomas CJ, Su XZ. PfCRT and PfMDR1 modulate interactions of artemisinin derivatives and ion channel blockers. Sci Rep. 2016 May 5;6:25379. doi: 10.1038/srep25379.

Mott BT, Eastman RT, Guha R, Sherlach KS, Siriwardana A, Shinn P, McKnight C, Michael S, Lacerda-Queiroz N, Patel PR, Khine P, Sun H, Kasbekar M, Aghdam N, Fontaine SD, Liu D, Mierzwa T, Mathews-Griner LA, Ferrer M, Renslo AR, Inglese J, Yuan J, Roepe PD, Su XZ, Thomas CJ. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations. Sci Rep. 2015 Sep 25;5:13891. doi: 10.1038/srep13891.

Public Health Impact

Development of novel chemical genomic platforms for the development of drugs for the treatment of pathogenic protozoa, and assay development to elucidate compound mechanism of action. These developments will be leveraged to support ongoing global efforts to reduce the impact that pathogenic protozoa have on infected individuals and to reduce economic, social and health burdens resulting from these infectious agents.