Ligands that targetsporozoite binding sites on cd81 and therapeutic methods using them

Abstract

The invention pertains to ligands that bind to CD81 and that inhibit or blockattachment to CD81, compositions and methods for preventing, inhibiting or treating infection byand ligands that target abinding 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 ofbinding. 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. Identification and design of groups of compounds that bind to CD81 for use as therapeutics for treating patients infected byand pathogens that interact with CD81. By binding to CD81, these molecules can block 1)attachment and entry into cells (infection), especially hepatocytes; 2) block or inhibit inflammatory responses caused by, and 3) block or inhibit the induction of other pathologies associated withinfection.