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

• Main Authors: Olga Chesnokov, Pimnitah Visitdesotrakul, Komal Kalani, Adel Nefzi, Andrew V. Oleinikov
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: International Journal of Molecular Sciences
• Subjects: <i>P. falciparum</i>; severe and cerebral malaria; small molecule inhibitors; combinatorial chemistry; mixture-based libraries; drug discovery
• Online Access: https://www.mdpi.com/1422-0067/22/11/5659

Specific adhesion of <i>P. falciparum</i> 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.