Viruses are small infectious agents, which combine several unique features in one system. Since self-replication is only possible inside living cells of other organisms, they have developed a sophisticated machinery to find their target cells, efficiently invade them and implement their genetic information in the transcription process of the host, while keeping him alive and metabolically active. These 4 achievements are exactly what scientist desire for any therapeutic transfection agents applicable to gene therapy. While various strategies have evolved to target cells, deliver genetic information into the cytosol by endosomal penetration (endosomal escape) and later to the nucleus for transcription the combination of such properties remains complex and synthetically challenging and complex. Thus, from a rational perspective one needs to complex the DNA, shield it against unspecific interactions and nucleases, and introduce functionalities to enable active targeting, endosomal escape as well as nuclear transport.<br/>Here we present a simple 3 step process in which we control the properties of such non-self-replicating synthetic viruses exclusively by block copolymer microstructure of reactive polypept(o)ides. The design of polymer microstructure was guided by molecular dynamics simulations of polyplex formation using a bead spring model and enabled us to define a tri- or tetrablock copolymer architecture, which efficiently complexes the nucleic acid while providing reactive side for the bio-reversible attachment of endosomolytic peptides. The synthesis, characterization and biological evaluation will be presented, demonstrating that this modular approach is able to yield core shell polyplexes, which are stable in human plasma, can be targeted to specific cell populations, transfect even non-dividing primary cells (bone marrow derived dendritic cells) and thus enable a novel class of pDNA vaccines for systemic application.

PeptoPlexes: Using tri- or tetrablock copolypept(o)ides for the synthesis of non-self-replicating synthetic viruses

255th National Meeting (2018)

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