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Bioorg Med Chem Lett. 2013 Oct 1;23(19):5356-60. doi: 10.1016/j.bmcl.2013.07.056. Epub 2013 Aug 2.

C-peptide inhibitors of Ebola virus glycoprotein-mediated cell entry: effects of conjugation to cholesterol and side chain-side chain crosslinking.

Author information

1
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Abstract

We previously described potent inhibition of Ebola virus entry by a 'C-peptide' based on the GP2 C-heptad repeat region (CHR) targeted to endosomes ('Tat-Ebo'). Here, we report the synthesis and evaluation of C-peptides conjugated to cholesterol, and Tat-Ebo analogs containing covalent side chain-side chain crosslinks to promote α-helical conformation. We found that the cholesterol-conjugated C-peptides were potent inhibitors of Ebola virus glycoprotein (GP)-mediated cell entry (~10(3)-fold reduction in infection at 40 μM). However, this mechanism of inhibition is somewhat non-specific because the cholesterol-conjugated peptides also inhibited cell entry mediated by vesicular stomatitis virus glycoprotein G. One side chain-side chain crosslinked peptide had moderately higher activity than the parent compound Tat-Ebo. Circular dichroism revealed that the cholesterol-conjugated peptides unexpectedly formed a strong α-helical conformation that was independent of concentration. Side chain-side chain crosslinking enhanced α-helical stability of the Tat-Ebo variants, but only at neutral pH. These result provide insight into mechanisms of C-peptide inhibiton of Ebola virus GP-mediated cell entry.

KEYWORDS:

C-peptide; Ebola virus; Hemorrhagic fever; Peptide design; Viral membrane fusion

PMID:
23962564
PMCID:
PMC3822755
DOI:
10.1016/j.bmcl.2013.07.056
[Indexed for MEDLINE]
Free PMC Article

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