Human　immunodeficiency　virus　type　1　(HIV-1),　the　pathogen　of　acquired　immunodeficiency　syndrome　(AIDS),　causes　about　2　million　people　to　death　every　year.　Fusion　inhibitors　targeted　the　envelope　protein　(gp41)　represent　a　novel　and　alternative　approach　for　anti-AIDS　therapy,　which　terminates　the　HIV-1　life　cycle　at　an　early　stage.　Using　CP621-652　as　a　template,　a　series　of　peptides　were　designed,　synthesized　and　evaluated　in　vitro　assays.　An　interesting　phenomenon　was　found　that　the　substitution　of　hydrophobic　residues　at　solvent　accessible　sites　could　increase　the　anti-HIV　activity　when　the　C-terminal　sequence　was　extended　with　an　enough　numbers　of　amino　acids.　After　the　active　peptides　was　synthesized　and　evaluated,　peptide　8　showed　the　best　anti-HIV-1　IIIB　whole　cell　activity　(MAGI　IC50　=　53.02　nM).　Further　study　indicated　that　peptide　8　bound　with　the　gp41　NHR　helix,　and　then　blocked　the　conformation　of　6-helix,　thus　inhibited　virus-cell　membrane　fusion.　The　results　would　be　helpful　for　the　design　of　peptide　fusion　inhibitors　against　HIV-1　infection.　(C)　2015　Elsevier　Ltd.　All　rights　reserved.