Schematic diagram of HIV-1 gp41 and its peptide derivatives. The gp41 numbering of HIV-1HXB2 is used. FP, fusion peptide; NHR, N-terminal heptad repeat; CHR, C-terminal heptad repeat; TRM, tryptophan-rich motif; TM, transmembrane domain; CT, cytoplasmic tail. The positions and sequences corresponding to the T-20-resistance mutation site and the pocket-forming site in the NHR are marked in blue. The positions and sequences of the M-T hook structure, pocket-binding domain (PBD), and tryptophan-rich motif (TRM) in the CHR are marked in green, red, and purple, respectively. Chol, C16, and C18 in parentheses represent cholesterol, palmitic acid, and stearic acid, respectively; PEG8 represents a flexible linker of 8-unit polyethylene glycol. Engineered residues in newly designed T-20 sequence-based lipopeptides are marked in pink.