Modular assembly of dimeric HIV fusion inhibitor peptides with enhanced antiviral potency.
Xiao J, Tolbert TJ., Bioorg Med Chem Lett., 2013, 23, 6046-51. doi: 10.1016/j.bmcl.2013.09.034. Epub 2013 Sep 20.
The HIV-1 envelope gp120/gp41 glycoprotein complex plays a critical role in virus-host cell membrane fusion and has been a focus for the development of HIV fusion inhibitors. In this Letter, we present the synthesis of dimers of HIV fusion inhibitor peptides C37H6 and CP32M, which target the trimeric gp41 in the pre-hairpin intermediate state to inhibit membrane fusion. Reactive peptide modules were synthesized using native chemical ligation and then assembled into dimers with varying linker lengths using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) ‘click’ chemistry. Cell-cell fusion inhibition assays demonstrated that dimers with a (PEG)7 linker showed enhanced antiviral potency over the corresponding monomers. Moreover, the bio-orthogonal nature of the CuAAC ‘click’ reaction provides a practical way to assemble heterodimers of HIV fusion inhibitors. Heterodimers consisting of the T20-sensitive strain inhibitor C37H6 and the T20-resistant strain inhibitor CP32M were produced that may have broader spectrum activities against both T20-sensitive and T20-resistant strains.
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