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000181524 037__ $$aDKFZ-2022-02059
000181524 041__ $$aEnglish
000181524 082__ $$a610
000181524 1001_ $$aCavazzini, Davide$$b0
000181524 245__ $$aEnhanced immunogenicity of a positively supercharged archaeon thioredoxin scaffold as a cell-penetrating antigen carrier for peptide vaccines.
000181524 260__ $$aLausanne$$bFrontiers Media$$c2022
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000181524 520__ $$aPolycationic resurfaced proteins hold great promise as cell-penetrating bioreagents but their use as carriers for the intracellular delivery of peptide immuno-epitopes has not thus far been explored. Here, we report on the construction and functional characterization of a positively supercharged derivative of Pyrococcus furiosus thioredoxin (PfTrx), a thermally hyperstable protein we have previously validated as a peptide epitope display and immunogenicity enhancing scaffold. Genetic conversion of 13 selected amino acids to lysine residues conferred to PfTrx a net charge of +21 (starting from the -1 charge of the wild-type protein), along with the ability to bind nucleic acids. In its unfused form, +21 PfTrx was readily internalized by HeLa cells and displayed a predominantly cytosolic localization. A different intracellular distribution was observed for a +21 PfTrx-eGFP fusion protein, which although still capable of cell penetration was predominantly localized within endosomes. A mixed cytosolic/endosomal partitioning was observed for a +21 PfTrx derivative harboring three tandemly repeated copies of a previously validated HPV16-L2 (aa 20-38) B-cell epitope grafted to the display site of thioredoxin. Compared to its wild-type counterpart, the positively supercharged antigen induced a faster immune response and displayed an overall superior immunogenicity, including a substantial degree of self-adjuvancy. Altogether, the present data point to +21 PfTrx as a promising novel carrier for intracellular antigen delivery and the construction of potentiated recombinant subunit vaccines.
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000181524 650_7 $$2Other$$aantigen carrier
000181524 650_7 $$2Other$$aepitope display
000181524 650_7 $$2Other$$aintracellular antigen delivery
000181524 650_7 $$2Other$$apeptide epitope
000181524 650_7 $$2Other$$aprotein DNA interaction
000181524 650_7 $$2Other$$aprotein scaffold engineering
000181524 650_7 $$2Other$$aprotein scaffold vaccine
000181524 650_7 $$2Other$$arecombinant vaccine
000181524 7001_ $$aSpagnoli, Gloria$$b1
000181524 7001_ $$0P:(DE-HGF)0$$aMariz, Filipe Colaco$$b2
000181524 7001_ $$aReggiani, Filippo$$b3
000181524 7001_ $$aMaggi, Stefano$$b4
000181524 7001_ $$aFranceschi, Valentina$$b5
000181524 7001_ $$aDonofrio, Gaetano$$b6
000181524 7001_ $$0P:(DE-He78)4cbf38280ce272e37f96081b070dd46a$$aMüller, Martin$$b7$$udkfz
000181524 7001_ $$aBolchi, Angelo$$b8
000181524 7001_ $$aOttonello, Simone$$b9
000181524 773__ $$0PERI:(DE-600)2606827-8$$a10.3389/fimmu.2022.958123$$gVol. 13, p. 958123$$p958123$$tFrontiers in immunology$$v13$$x1664-3224$$y2022
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000181524 9141_ $$y2022
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