Small Molecule Compounds Identified from Mixture-Based Library Inhibit Binding between Plasmodium falciparum Infected Erythrocytes and Endothelial Receptor ICAM-1.

Adel Nefzi,Olga Chesnokov,Pimnitah Visitdesotrakul,Andrew V Oleinikov,Komal Kalani

doi:10.3390/ijms22115659

Abstract

Specific adhesion of P. falciparum parasite-infected erythrocytes (IE) in deep vascular beds can result in severe complications, such as cerebral malaria, placental malaria, respiratory distress, and severe anemia. Cerebral malaria and severe malaria syndromes were associated previously with sequestration of IE to a microvasculature receptor ICAM-1. The screening of Torrey Pines Scaffold Ranking library, which consists of more than 30 million compounds designed around 75 molecular scaffolds, identified small molecules that inhibit cytoadhesion of ICAM-1-binding IE to surface-immobilized receptor at IC50 range down to ~350 nM. With their low cytotoxicity toward erythrocytes and human endothelial cells, these molecules might be suitable for development into potentially effective adjunct anti-adhesion drugs to treat cerebral and/or severe malaria syndromes. Our two-step high-throughput screening approach is specifically designed to work with compound mixtures to make screening and deconvolution to single active compounds fast and efficient.

Highlights

Malaria caused by Plasmodium falciparum parasite is one of the major deadly diseases in the world, with a yearly count of half a billion cases and 0.4 million deaths, mostly among young children [1]
Cytoadherence [4,5,6] plays an important role in the lifecycle and virulence of P. falciparum, the deadliest of human malaria species, and is a cause of at least placental malaria (PM) [7] and cerebral malaria (CM) [8,9,10,11,12]
As the screened library was small in size, which significantly limits the number of active hits, we identified compounds with a modest IC50 values in micromolar range

Summary

Introduction

Malaria caused by Plasmodium falciparum parasite is one of the major deadly diseases in the world, with a yearly count of half a billion cases and 0.4 million deaths, mostly among young children [1]. Most deaths result from severe malaria (SM) complications that include cerebral malaria (CM), placental malaria (PM), respiratory distress, and severe anemia. Though efficient anti-malarial drugs rapidly kill parasites, significant mortality (10–15%) still results from SM even in hospital admissions, within 24 h, likely because continued cytoadherence of infected erythrocytes (IE) long after the parasite has been killed [3]. Cytoadherence [4,5,6] plays an important role in the lifecycle and virulence of P. falciparum, the deadliest of human malaria species, and is a cause of at least placental malaria (PM) [7] and cerebral malaria (CM) [8,9,10,11,12]

Methods

Results

Discussion

Conclusion