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Swapped-Domain Constructs of the Glycoprotein-41 Ectodomain Are Potent Inhibitors of HIV Infection
journal contribution
posted on 2015-05-15, 00:00 authored by Shidong Chu, Hardeep Kaur, Ariana Nemati, Joseph
D. Walsh, Vivian Partida, Shao-Qing Zhang, Miriam GochinThe
conformational rearrangement of N- and C-heptad repeats (NHR,
CHR) of the HIV-1 glycoprotein-41 (gp41) ectodomain into a trimer
of hairpins triggers virus–cell fusion by bringing together
membrane-spanning N- and C-terminal domains. Peptides derived from
the NHR and CHR inhibit fusion by targeting a prehairpin intermediate
state of gp41. Typically, peptides derived from the CHR are low nanomolar
inhibitors, whereas peptides derived from the NHR are low micromolar
inhibitors. Here, we describe the inhibitory activity of swapped-domain
gp41 mimics of the form CHR–loop–NHR, which were designed
to form reverse hairpin trimers exposing NHR grooves. We observed
low nanomolar inhibition of HIV fusion in constructs that possessed
the following properties: an extended NHR C-terminus, an exposed conserved
hydrophobic pocket on the NHR, high helical content, and trimer stability.
Low nanomolar activity was independent of CHR length. CD studies in
membrane mimetic dodecylphosphocholine micelles suggested that bioactivity
could be related to the ability of the inhibitors to interact with
a membrane-associated prehairpin intermediate. The swapped-domain
design resolves the problem of unstable and weakly active NHR peptides
and suggests a different mechanism of action from that of CHR peptides
in inhibition of HIV-1 fusion.