Model peptide and protein systems used in discovery and study of HIV-1 gp41 fusion protein inhibitors. (a) IQN17 mimics the inner core and is derived from a portion of the gp41 HR1 region linked to a trimerization domain derived from GCN4. It was used to validate compounds that prevent binding of PIE7 peptides to the inner core cavity. (40, 41) (b) gp41–5 contains three HR1 peptides and two HR2 peptides derived from gp41 and was used to identify compounds that prevent binding of a fluorescently labeled HR2 peptide (44, 45). (c) gp41-inter mimics the prefusion prehairpin intermediate and was used to identify compounds that prevent binding of Fab 2F5 to the MPER (47, 48). (d) Map of the portions of gp41 present in IQN17, gp41–5, and gp41-inter. Abbreviations: CT, cytoplasmic tail; Fab, fluorescence-labeled antigen-binding fragment; FP, fusion peptide; HIV-1, human immunodeficiency virus type 1; HR, heptad repeat; MPER, membrane-proximal external region; TMD, transmembrane domain. Figure adapted from images created with BioRender.com.