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J. Biol. Chem., Vol. 276, Issue 2, 1391-1397, January 12, 2001
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From the DP178, a synthetic peptide corresponding to a
segment of the transmembrane envelope glycoprotein (gp41) of human
immunodeficiency virus, type 1 (HIV-1), is a potent inhibitor of viral
infection and virus-mediated cell-cell fusion. Nevertheless, DP178 does not contain gp41 coiled-coil cavity binding residues postulated to be
essential for inhibiting HIV-1 entry. We find that DP178 inhibits
phospholipid redistribution mediated by the HIV-1 envelope glycoprotein
at a concentration 8 times greater than that of solute redistribution
(the IC50 values are 43 and 335 nM,
respectively). In contrast, C34, a synthetic peptide which
overlaps with DP178 but contains the cavity binding residues, did not
show this phenomenon (11 and 25 nM, respectively). The
ability of DP178 to inhibit membrane fusion at a post-lipid mixing
stage correlates with its ability to bind and oligomerize on the
surface of membranes. Furthermore, our results are consistent with a
model in which DP178 inhibits the formation of gp41 viral hairpin
structure at low affinity, whereas C34 inhibits its formation at high
affinity: the failure to form the viral hairpin prevents both lipid and
solute from redistributing between cells. However, our data also
suggest an additional membrane-bound inhibitory site for DP178 in the
ectodomain of gp41 within a region immediately adjacent to the
membrane-spanning domain. By binding to this higher affinity site,
DP178 inhibits the recruitment of several gp41-membrane complexes, thus
inhibiting fusion pore formation.
Mode of Action of an Antiviral Peptide from HIV-1
INHIBITION AT A POST-LIPID MIXING STAGE*
§,,,
Department of Biological Chemistry, The
Weizmann Institute of Science, Rehovot, 76100 Israel and the
¶ Laboratory of Experimental and Computational Biology, NCI,
National Institutes of Health, Frederick, Maryland 21702-1201
*
This work was supported by the National Institutes of Health
intramural AIDS targeted antiviral program.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Harold S. and Harriet B. Brady Professorial
Chair in Cancer Research. To whom correspondence should be addressed: Dept. of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100 Israel. Tel.: 972-8-9342711; Fax: 972-8-9344112; E-mail:
Yechiel.Shai@weizmann.ac.il.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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