Novel Recombinant Engineered gp41 N-terminal Heptad Repeat Trimers and Their Potential as Anti-HIV-1 Therapeutics or Microbicides

Novel recombinant engineered gp 41 N - terminal heptad - repeat trimers : potential as anti - HIV - 1 therapeutics or microbicides

Peptides derived from N-terminal heptad repeat (NHR) of the HIV-1 gp41 are generally poor inhibitors of HIV-1 entry because these peptides tend to aggregate and do not form a trimeric coiled coil. In this study, we have fused portions of gp41 NHR, e.g., N36 or N28, to the T4 fibritin trimerization domain, Foldon (Fd), thus constructing novel NHR-trimers, designated N36Fd or N28Fd, which could b...

Single-chain protein mimetics of the N-terminal heptad-repeat region of gp41 with potential as anti-HIV-1 drugs.

During HIV-1 fusion to the host cell membrane, the N-terminal heptad repeat (NHR) and the C-terminal heptad repeat (CHR) of the envelope subunit gp41 become transiently exposed and accessible to fusion inhibitors or Abs. In this process, the NHR region adopts a trimeric coiled-coil conformation that can be a target for therapeutic intervention. Here, we present an approach to rationally design ...

Site-specific Isopeptide Bridge Tethering of Chimeric gp41 N-terminal Heptad Repeat Helical Trimers for the Treatment of HIV-1 Infection

Peptides derived from the N-terminal heptad repeat (NHR) of HIV-1 gp41 can be potent inhibitors against viral entry when presented in a nonaggregating trimeric coiled-coil conformation via the introduction of exogenous trimerization motifs and intermolecular disulfide bonds. We recently discovered that crosslinking isopeptide bridges within the de novo helical trimers added exceptional resistan...

Mutations of Gln64 in the HIV-1 gp41 N-terminal heptad repeat render viruses resistant to peptide HIV fusion inhibitors targeting the gp41 pocket.

To prove that the peptidic HIV-1 fusion inhibitors containing the pocket-binding domain (PBD) mainly target the hydrophobic pocket in the gp41 N-terminal heptad repeat (NHR), we constructed pseudoviruses by replacement of Q64 in the gp41 pocket region with Ala (Q64A) or Leu (Q64L). These viruses were highly resistant to C34 and CP32M containing the PBD, while they were susceptible to T20 (enfuv...

Conserved Salt-bridge between the N- and C-Terminal Heptad Repeat Regions of HIV-1 gp41 Core Structure Is Critical for Virus Entry and Inhibition