The essential malaria protein Pf CyRPA targets glycans to invade erythrocytes

Plasmodium falciparum is a human -adapted apicomplexan parasite that causes the most dangerous form of malaria. P. falciparum cysteine-rich protective antigen ( Pf CyRPA) is an invasion complex protein essential for erythrocyte invasion. The precise role of Pf CyRPA in this process has not been resolved. Here, we show that Pf CyRPA is a lectin targeting glycans terminating with a2 -6 -linked N-acetylneuraminic acid (Neu5Ac). Pf CyRPA has a >50 -fold binding preference for human, a2 -6 -linked Neu5Ac over non -human, a2 -6 -linked N-glycolylneuraminic acid. Pf CyRPA lectin sites were predicted by molecular modeling and validated by mutagenesis studies. Transgenic parasite lines expressing endogenous Pf CyRPA with single amino acid exchange mutants indicated that the lectin activity of Pf CyRPA has an important role in parasite invasion. Blocking Pf CyRPA lectin activity with small molecules or with lectin-site-specific monoclonal antibodies can inhibit blood -stage parasite multiplication. Therefore, targeting Pf CyRPA lectin activity with drugs, immunotherapy, or a vaccine -primed immune response is a promising strategy to prevent and treat malaria.