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• W1506903399 abstract "Viruses are naturally formed bionanoparticles (BNPs), ranging in size from 22-150 nm. Remarkably, small viruses are composed of one single protein chain folding into a capsid structure with icosahedral symmetry. The icosahedron is built up from 60 asymmetric units and is the largest closed shell in which every subunit is in an identical environment. It is characterized by 2-fold, 3-fold and 5-fold rotational symmetry axes. By superposition of different protein oligomerization domains onto the symmetry axes of the icosahedron, a nanoparticle with icosahedral symmetry can be designed. To test our concept, we have designed a peptide comprising a slightly modified form of a pentameric coiled-coil domain of cartilage oligomeric matrix protein (COMP) linked to a de novo designed trimeric coiled-coil domain as a single chain. These two different oligomeric domains were linked by two glycine residues to provide flexibility between them and were fixed in their relative orientation with an intramolecular disulfide bridge. Computer modeling predicted that such a design would result in an icosahedral peptide based nanoparticle with a diameter of 17 nm. We chemically synthesized the above designed peptide and performed refolding studies and biophysical characterization using analytical ultra centrifugation (AUC) and electron microscopy (EM), thereby showing the formation of icosahedral nanoparticles with a diameter of ~ 17 nm. Subsequently, we switched to recombinant expression of the designed peptide. Again, we performed refolding studies with the expressed peptide and biophysical characterization (AUC and EM), thereby showing the formation of icosahedral nanoparticles with a diameter of ~ 17 nm. In addition, we showed that during refolding, parameters such as ionic strength, pH of the refolding buffer and presence of glycerol influence the formation of icosahedral nanoparticles. Moreover, we observed icosahedral nanoparticles in conditions in which the formation of intramolecular disulfide bridges is not possible. This showed that even in the absence of intramolecular disulfide bridge the helices of the two different oligomeric domains like to be arranged close to each other, as this will favor the formation of icosahedral nanoparticles.In parallel, we also modified the designed peptide to include charged residues at theinterface between the two oligomeric domains. The idea was to fix the relative orientationbetween the two oligomeric domains through ionic interactions. The subsequentexpression, refolding studies and biophysical characterization showed the formation ofnanoparticles, but they were lacking icosahedral symmetry. This result showed that thedesign has to be optimized further to obtain icosahedral nanoparticles.Moreover, we wanted to study whether in our design principles oligomerization motifsother than coiled-coils can be used to form icosahedral nanoparticles. Accordingly, weused globular foldon domain as the trimerization domain and the COMP as thepentamerization domain. The results showed the formation of nanoparticles, but theywere lacking icosahedral symmetry. In addition, in the above design we studied the effectof linker region by increasing the liker region to four and six residues, but it did not helpin the formation of icosahedral nanoparticles. However, when the foldon domainextended with the trimeric coiled-coil domain as a single trimerization domain and withCOMP as the penatmerization domain, we observed icosahedral nanoparticles.Viruses are known for their induction of strong antibody (B-cell) mediated immuneresponse in the host even against the self-antigens. This property is conferred by therepetitive arrangement of the antigens on their surface. Peptide based nanoparticles havesimilar properties to viruses, such as self-assembly and most importantly the repetitivearrangement of subunits (peptide based nanoparticles are composed of 60 identicalmonomeric chains). Therefore, we wanted to use our system as a ‘repetitive antigendisplay carrier’ in vaccination, as an alternative to viral and viral based platforms such asvirus like particles (VLPs). To this end, and in order to understand the effect of ournanoparticle size on immune response, we built different constructs displaying the pilinepitope of Pseudomonas pathogen at their C-terminus. Computer modeling indicated thatthese constructs would form icosahedral nanoparticles of three sizes: small (18 nm),medium (23 nm) and large (29 nm). From the refolding studies, we observed mostlyaggregation and precipitation of the nanoparticles.This effect presumably due to interparticle cross-linking, by the cysteine residues ofpilin epitope which are present at the periphery of nanoparticles, as we observedaggregation of small size icosahedral nanoparticles upon changing from reducing tooxidizing condition. Immunization results, because of the aggregation and precipitationbehavior of nanoparticles, showed poor immune response. However, the immunizationresults showed that our nanoparticles present the attached epitope in their native form, aswe observed binding against native pilin protein. Moreover, immunization results fromour laboratory using medium size nanoparticles displaying Salmonella epitope D2showed promising results, as we got antibody titer values which were well comparable tothe values obtained with VLPs. This places our system alongside with VLPs, which are inclinical trials as a carrier in vaccination." @default.
• W1506903399 created "2016-06-24" @default.
• W1506903399 creator A5060617891 @default.
• W1506903399 date "2008-01-01" @default.
• W1506903399 modified "2023-09-27" @default.
• W1506903399 title "Design and analysis of peptide based nanoparticles" @default.
• W1506903399 doi "https://doi.org/10.5451/unibas-004642021" @default.
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