Nucleic acids Large molecules composed structure

Ideas on the three-dimensional structure of proteins were no less preliminary. It was agreed that they were big molecules - macromolecules - probably composed of linear chains of amino acids of up to 100 or more. But just how their primary sequences were determined, how they were synthesized, and how they arrived at their native three-dimensional conformations was a complete mystery (Hunter, 2000, ch. 11). It is a testimony to how little was known about protein function that a majority of biochemists considered that it was proteins, rather then nucleic acids, that played the primary role in heredity and formed the basic aperiodic molecule that made up the material structure of the gene (McCarty, 2003j. The question of whether proteins represented a potentially infinite set of Lego -like assemblages, largely unconstrained by physical law and determined by natural selection, or whether they represented a finite set of natural forms determined mainly by natural law and therefore were antecedent to life and evolution (like a set of atoms or crystals), was simply impossible to answer. 

Although asDNA and siRNA finish their journey at the cytosol just after endosomal escape, other nucleic acid drugs such as pDNA must be delivered through the cytosol into the nucleus for the transcription of the therapeutic gene. Cytosol is not a simple liquid phase that enables free diffusion of macromolecules, but a gel-like phase with a fine mesh structure primarily composed of actin filaments [42]. The diffusion rate of large molecules over a hydrodynamic diameter of 85 nm is significantly lower than that of small molecules in cytosol due to the molecular exclusion effect [43]. In addition, the cytosolic concentration of free DNA was shown to rapidly decrease, with a half-life of 90 min, by the action of nucleases preventing the invasion of viral DNA or RNA [44]. Hence, protection of pDNA from nuclease attack is needed for delivery to the nucleus without loss of activity. 

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