title: The N-Terminal T-T Motif of a Third-Generation HIV-1 Fusion Inhibitor Is Not Required for Binding Affinity and Antiviral Activity.
abstract: The highlighted next-generation HIV-1 fusion inhibitor peptide 1 is capped by two threonines. Here, we generated peptide 2 by deleting the T-T motif and compared their structural and antiviral properties. Significantly, two peptides showed similar helical and oligomeric states in solution, comparable binding affinities to the target, and no significant difference to inhibit HIV-1 fusion and infection. Also, the T-T motif was not associated with peptide 1 resistant mutations and its deletion did not affect peptide 1 against enfuvirtide-resistant HIV-1 mutants. The redundancy of the T-T motif was further verified by the model peptide C34 and short peptide inhibitors that mainly target the gp41 pocket, suggesting that the N-terminal T-T motif of peptide 1 could be removed or modified toward the development of new anti-HIV-1 drugs. Consistently, our data have verified that the M-T hook structure rather than the T-T motif is an efficient strategy for short peptide fusion inhibitors.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , No. 9, Dong Dan San Tiao, Beijing 100730, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Chong
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , No. 9, Dong Dan San Tiao, Beijing 100730, China.
authors.forename: Zonglin
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , No. 9, Dong Dan San Tiao, Beijing 100730, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College , No. 9, Dong Dan San Tiao, Beijing 100730, China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002459:Cell Fusion; D024921:Drug Resistance, Multiple, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide