Dataset Information

High-throughput screening platform identifies small molecules that prevent sequestration of Plasmodium falciparum-infected erythrocytes.

ABSTRACT:

Background

We developed a 2-step approach to screen molecules that prevent and/or reverse Plasmodium falciparum-infected erythrocyte (IE) binding to host receptors. IE adhesion and sequestration in vasculature causes severe malaria, and therefore antiadhesion therapy might be useful as adjunctive treatment. IE adhesion is mediated by the polymorphic family (approximately 60 members) of P. falciparum EMP1 (PfEMP1) multidomain proteins.

Methods

We constructed sets of PfEMP1 domains that bind ICAM-1, CSA, or CD36, receptors that commonly support IE binding. Combinations of domain-coated beads were assayed by Bio-Plex technology as a high-throughput molecular platform to screen antiadhesion molecules (antibodies and small molecules). Molecules identified as so-called hits in the screen (first step) then could be assayed individually for inhibition of binding of live IE to receptors (second step).

Results

In proof-of-principle studies, the antiadhesion activity of several antibodies was concordant in Bio-Plex and live IE assays. Using this 2-step approach, we identified several molecules in a small molecule library of 10 000 compounds that could inhibit and reverse binding of IEs to ICAM-1 and CSA receptors.

Conclusion

This 2-step screening approach should be efficient for identification of antiadhesion drug candidates for falciparum malaria.

SUBMITTER: Gullingsrud J

PROVIDER: S-EPMC4366606 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

High-throughput screening platform identifies small molecules that prevent sequestration of Plasmodium falciparum-infected erythrocytes.

Gullingsrud Justin J Milman Neta N Saveria Tracy T Chesnokov Olga O Williamson Kathryn K Srivastava Anand A Gamain Benoit B Duffy Patrick E PE Oleinikov Andrew V AV

The Journal of infectious diseases 20141029 7

<h4>Background</h4>We developed a 2-step approach to screen molecules that prevent and/or reverse Plasmodium falciparum-infected erythrocyte (IE) binding to host receptors. IE adhesion and sequestration in vasculature causes severe malaria, and therefore antiadhesion therapy might be useful as adjunctive treatment. IE adhesion is mediated by the polymorphic family (approximately 60 members) of P. falciparum EMP1 (PfEMP1) multidomain proteins.<h4>Methods</h4>We constructed sets of PfEMP1 domains ...[more]

PMID: 25355939

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Dataset Information

High-throughput screening platform identifies small molecules that prevent sequestration of Plasmodium falciparum-infected erythrocytes.

Background

Methods

Results

Conclusion

Publications

High-throughput screening platform identifies small molecules that prevent sequestration of Plasmodium falciparum-infected erythrocytes.

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