Immunogenicity of DNA vaccines can be efficiently improved by adding adjuvants into their formulations. In this regard, the application of nano- and microparticles as vaccines adjuvants, or delivery systems, provides a powerful tool in designing modern vaccines. In the present study, we examined the role of “Supramolecular Hacky Sacks” (SHS) particles, made via the hierarchical self-assembly of a guanosine derivative, as a novel immunomodulator for DNA plasmid preparations. These plasmids code for the proteins HIV-1 Gag (pGag), the wild-type vaccinia virus Western Reserve A27 (pA27L), or a codon-optimized version of the latter (pOD1A27Lopt), which is also linked to the sequence of the outer domain-1 (OD1) from HIV-1 gp120 protein. We evaluated the enhancement of the immune responses generated by our DNA plasmid formulations in a murine model through ELISpot and ELISA assays. The SHS particles increased the frequencies of IFN-γ-producing cells in mice independently immunized with pGag and pA27L plasmids. Moreover, the addition of SHS to pGag and pA27L DNA plasmid formulations enhanced the production of IFN-γ (Th1-type) over IL-4 (Th2-type) cellular immune responses. Furthermore, pGag and pA27L plasmids formulated with SHS, triggered the production of antigen-specific IgG in mice, especially the IgG2a isotype. However, no improvement of either of those adaptive immune responses was observed in mice receiving pOD1A27Lopt+SHS. Here, we demonstrated that SHS particles have the ability to improve both arms of adaptive immunity of plasmid coding “wild-type” antigens without additional strategies to boost their immunogenicity. To the best of our knowledge, this is the first report of SHS guanosine-based particles as DNA plasmid adjuvants.
Guanosine and related derivatives self-assemble in the presence of cations like potassium into supramolecular G-quadruplexes (SGQs), where four guanine moieties form planar tetrads (T) that coaxially stack into columnar aggregates with broad size distributions. However, SGQs made from 8-aryl-2’-deoxyguanosine derivatives (8ArGs), form mostly octamers, or two-tetrad (2T)-SGQs, while some form dodecamers (3T-SGQs), or hexadecamers (4T-SGQs), and none reported to date form higher assemblies. A theoretical model that addresses the configurational space available for the multiple pathways available for 8ArGs to self-assemble into SGQs is used to frame a series of molecular dynamics simulations (MDS) with selected SGQs. Some key insights from this work include: (a) The predicted entropic costs are not significantly higher for SGQs with more subunits due to their hierarchical assembly pathways; (b) The multiple isomeric SGQs vary in the interfacial contacts between consecutive tetrads, due to their two distinct sides (head, h; tail, t), with the MDS supporting the predicted order of stability of hh > ht > tt for octamers. (c) Such order also applies to dodecamers and hexadecamers, but with context-dependent exceptions due to strong allosteric effects. (d) The main factor disfavoring the tt interface is the repulsive dipolar interactions between the O4’ from ribose moieties on adjacent tetrads. (e) SGQs with 5 or more tetrads are disfavored because the attractive interactions are not large or strong enough to overcome the many repulsive forces resulting from the addition of further tetrads. We expect these findings provide some guidelines to enable the further development of SGQs into functional materials.
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