Format

Send to

Choose Destination
Biochemistry. 2007 Apr 10;46(14):4360-9. Epub 2007 Mar 20.

Protein design of a bacterially expressed HIV-1 gp41 fusion inhibitor.

Author information

1
Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA.

Abstract

Peptides derived from the carboxyl-terminal heptad repeat of the gp41 envelope glycoprotein ectodomain (C-peptides) can inhibit HIV-1 membrane fusion by binding to the amino-terminal trimeric coiled coil of the same protein. The fusion inhibitory peptide T-20 contains an additional tryptophan-rich sequence motif whose binding site extends beyond the gp41 coiled-coil region yet provides the key determinant of inhibitory activity in T-20. Here we report the design of a recombinant peptide inhibitor (called C52L) that includes both the C-peptide and tryptophan-rich regions. By calorimetry, C52L binds to a peptide mimic of the amino-terminal coiled coil with a Kd of 80 nM, reflecting the large degree of helicity in C52L as measured by circular dichroism spectroscopy. The C52L peptide potently inhibits in vitro infection of human T cells by diverse primary HIV-1 isolates irrespective of coreceptor preference, with nanomolar IC50 values. Significantly, C52L is fully active against T-20-resistant variants in a single-cycle HIV-1 infectivity assay. Moreover, because it can be expressed in bacteria, the C52L peptide might be more economical to manufacture on a large scale than T-20-like peptides produced by chemical synthesis. Hence the C52L fusion inhibitor may find a practical application, for example as a vaginal or rectal microbicide to prevent HIV-1 infection in the developing world.

PMID:
17371053
DOI:
10.1021/bi7001289
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center