title: Identification of a critical motif for the human immunodeficiency virus type 1 (HIV-1) gp41 core structure: implications for designing novel anti-HIV fusion inhibitors.
abstract: Human immunodeficiency virus type 1 (HIV-1) entry into the host cell involves a cascade of events and currently represents one of most attractive targets in the search for new antiviral drugs. The fusion-active gp41 core structure is a stable six-helix bundle (6-HB) folded by its trimeric N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). Peptides derived from the CHR region of HIV-1 gp41 are potent fusion inhibitors that target the NHR to block viral and cellular membrane fusion in a dominant negative fashion. However, all CHR peptides reported to date are derived primarily from residues 628 to 673 of gp41; little attention has been paid to the upstream sequence of the pocket binding domain (PBD) in the CHR. Here, we have identified a motif ((621)QIWNNMT(627)) located at the upstream region of the gp41 CHR, immediately adjacent to the PBD ((628)WMEWEREI(635)). Biophysical characterization demonstrated that this motif is critical for the stabilization of the gp41 6-HB core. The peptide CP621-652, containing the (621)QIWNNMT(627) motif, was able to interact with T21, a counterpart peptide derived from the NHR, to form a typical 6-HB structure with a high thermostability (thermal unfolding transition [T(m)] value of 82 degrees C). In contrast, the 6-HB formed by the peptides N36 and C34, which has been considered to be a core structure of the fusion-active gp41, had a T(m) of 64 degrees C. Different from T-20 (brand name Fuseon), which is the first and only HIV-1 fusion inhibitor approved for clinical use, CP621-652 could efficiently block 6-HB formation in a dose-dependent manner. Significantly, CP621-652 had potent inhibitory activity against HIV-1-mediated cell-cell fusion and infection, especially against T-20- and C34-resistant virus. Therefore, our works provide important information for understanding the core structure of the fusion-active gp41 and for designing novel anti-HIV peptides.
authors.affiliation: AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. heyuxian@yahoo.com
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.forename: Jianwei
authors.initials: J
authors.lastname: Cheng
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.forename: Zhi
authors.initials: Z
authors.lastname: Qi
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Mingxin
authors.initials: M
authors.lastname: Dong
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Dai
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics*; D000595:Amino Acid Sequence; D002850:Chromatography, Gel; D002942:Circular Dichroism; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1