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Published Online January 11, 2001
Science DOI: 10.1126/science.1057453

Reports

Submitted on November 14, 2000
Accepted on December 18, 2000

Protein Design of an HIV-1 Entry Inhibitor

Michael J. Root 1, Michael S. Kay 2, Peter S. Kim 3*

1 Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA
2 Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA
3 Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA. Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA.

* To whom correspondence should be addressed. E-mail: kimadmin{at}wi.mit.edu.

HIV-1 membrane fusion is promoted by the formation of a trimer-of-hairpins structure that brings the amino- and carboxyl-terminal regions of the gp41 envelope glycoprotein ectodomain into close proximity. Peptides derived from the carboxyl-terminal region (C-peptides) potently inhibit HIV-1 entry by binding to the gp41 amino-terminal region. To test the converse of this inhibitory strategy we designed a small protein, denoted 5-Helix, that binds the C-peptide region of gp41. The 5-Helix displays potent (nanomolar) inhibitory activity against diverse HIV-1 variants, and may serve as the basis for a new class of anti-viral agents. The inhibitory activity of 5-Helix also suggests a strategy for generating an HIV-1 neutralizing antibody response targeting the carboxyl-terminal region of the gp41 ectodomain.


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