Using tethered sub-100 nm lipid vesicles that mimic enveloped viruses with nanoscale membrane curvature, we have in this Work designed a total internal reflection fluorescence microscopy-based single assay to investigate how an antiviral amphipathic alpha-helical (AH) peptide interacts with lipid membranes to induce membrane curvature-dependent. pore formation. and membrane destabilization. Based on a combination of statistics from single vesicle imaging, binding kinetics data, and theoretical analysis, we propose a mechanistic model that is consistent with the experimentally observed peptide association and pore formation kinetics at medically relevant peptide concentrations (10 nM to 1 mu M) and unusually low peptide-to-lipid (P/L), ratio (similar to 1/1000). Importantly, the preference of the AH peptide to selectively rupture virions with sub-100 nm diameters appears to be related to membrane strain-dependent pore formation rather than to previously observed nanoscale membrane. curvature facilitated binding of AH peptides. Compared to other known. proteins and peptides, the combination of low effective P/L ratio and high specificity for nm-sized membrane curvature lends this particular AH peptide great potential to serve as a framework for developing a highly specific and potent antiviral agent for prophylactic and therapeutic applications while avoiding toxic side effects against host cell membranes.
机构:
Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Bobardt, Michael D.
Cheng, Guofeng
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Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Cheng, Guofeng
de Witte, Lot
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Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol & Immunol, NL-1081 BT Amsterdam, NetherlandsScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
de Witte, Lot
Selvarajah, Suganya
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Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Selvarajah, Suganya
Chatterji, Udayan
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Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Chatterji, Udayan
Sanders-Beer, Brigitte E.
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BIOQUAL Inc, Rockville, MD 20850 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Sanders-Beer, Brigitte E.
Geijtenbeek, Teunis B. H.
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Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol & Immunol, NL-1081 BT Amsterdam, NetherlandsScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Geijtenbeek, Teunis B. H.
Chisari, Francis V.
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Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Chisari, Francis V.
Gallay, Philippe A.
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Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Cho, Nam-Joon
Cho, Sang-Joon
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机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Cho, Sang-Joon
Cheong, Kwang Ho
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机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Cheong, Kwang Ho
Glenn, Jeffrey S.
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Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USAStanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Glenn, Jeffrey S.
Frank, Curtis W.
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机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
机构:
Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Bobardt, Michael D.
Cheng, Guofeng
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h-index: 0
机构:
Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Cheng, Guofeng
de Witte, Lot
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h-index: 0
机构:
Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol & Immunol, NL-1081 BT Amsterdam, NetherlandsScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
de Witte, Lot
Selvarajah, Suganya
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h-index: 0
机构:
Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Selvarajah, Suganya
Chatterji, Udayan
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Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Chatterji, Udayan
Sanders-Beer, Brigitte E.
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h-index: 0
机构:
BIOQUAL Inc, Rockville, MD 20850 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Sanders-Beer, Brigitte E.
Geijtenbeek, Teunis B. H.
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h-index: 0
机构:
Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol & Immunol, NL-1081 BT Amsterdam, NetherlandsScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Geijtenbeek, Teunis B. H.
Chisari, Francis V.
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h-index: 0
机构:
Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
Chisari, Francis V.
Gallay, Philippe A.
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h-index: 0
机构:
Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USAScripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Cho, Nam-Joon
Cho, Sang-Joon
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h-index: 0
机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Cho, Sang-Joon
Cheong, Kwang Ho
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h-index: 0
机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Cheong, Kwang Ho
Glenn, Jeffrey S.
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h-index: 0
机构:
Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USAStanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA
Glenn, Jeffrey S.
Frank, Curtis W.
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h-index: 0
机构:Stanford Univ, Dept Med, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA