Abstract: The invention pertains to ligands that bind to CD81 and that inhibit or block Plasmodium attachment to CD81, compositions and methods for preventing, inhibiting or treating infection by Plasmodium and ligands that target a Plasmodium binding site on CD81 and methods of making and using them. A series of ligand binding sites on the large extracellular loop of the open conformation of CD81 have been identified. Several important sites were located in regions identified by mutational studies to be the site of Plasmodium binding. Ligands that recognize these sites were identified. Linking together two or three ligands that bind with low or moderate affinities to different structurally unique sites on a target protein were used to generate small molecule ligand conjugates that exhibit very high affinities to their CD81 targets. Hybrid ligand molecules were also designed using fragment-based drug design methods to generate analogs of the ligands that bind more tightly to the protein than the parent compounds.