Nucleic acids, stability

NUCLEIC ACID STABILITY GENERAL CONSIDERATIONS AND IMPROVEMENT... 

Nucleic acid stabilization, electrostatics, structure and potential stabilization or catalysis in enzymes... 

Stereoelectronic Factors that Affect Nucleic Acid Stability 665... 

Freier. S.M. Altmann, K.-H. The ups and downs of nucleic acid stability Structure-stability studies on chemically-modified DNA RNA complexes. Nucl. Acids Res. 1997. 

Nucleic acid stability at different pH values is also a consideration. At pH < 2,... 

Closer examination of thermal denaturation reveals some of the chemical factors that determine protein and nucleic acid stability. For example, the thermal stability of DNA increases with the number of C-G base pairs in the sequence because each C-G base pair has three hydrogen bonds (1), whereris each T-A base pair has only two (2). More energy is required to unravel a double hehx that has a higher proportion of hydrogen bonding interactions per base pair. 

The nature of the zeta potential of the resulting DNA-nanoparticle structures (either positive or negative) may also be a determinant of the route of administration, toxicity or nucleic acid stability. A positive zeta potential seems to be very important for increasing the interactions between nanoparticles and the cell surface and is usually associated with more effective transfection systems. However, negative zeta potentials are required in order to avoid certain undesirable interactions with the biological environment that can lead to system instability and side effects. 

Most of the compounds mentioned above are electrically neutral and therefore poorly soluble in water at neutral pH. There are exceptions, such as poly (9-vinyladenine), and poly(l-vinyluracil). All compounds are stable to chemical and enzymatic hydrolysis, and they form complexes with complementary polynucleotides. However, these complexes do not have the simple stoichiometry found in natural nucleic acids. Stability and stoichiometry of complexes do depend on solvent, temperature, and pH of the system (36). Again, because of the complexity of the field, the reader is referred to the review articles mentioned above (36-38). Poly(A -vinyl) derivatives have been carefully tested for their biological and antiviral activity by Pitha (38) in enzyme assays, cell cultures, and in organisms. 

An understanding of a wide variety of phenomena concerning conformational stabilities and molecule-molecule association (protein-protein, protein-ligand, and protein-nucleic acid) requires consideration of solvation effects. In particular, a quantitative assessment of the relative contribution of hydrophobic and electrostatic interactions in macromolecular recognition is a problem of central importance in biology. 

A correlation of enhanced synthesis of polyamines with rapid growth or cell proliferation has been observed 21. From a physiological point of view, polyamines are implicated as regulators of cell proliferative activity 22). It is well known that polyamines, as protonated polycations, can bind with nucleotide and nucleic acid anions 23 241 to affect biochemical reactivities and stabilize tertiary structures 25,26). 

Virus maturation and assembly at the cell membrane or the nuclear membrane has long been seen as a potential target for antiviral compounds. For the virus to mature and be released in a conformation that will insure stability and survival of the viral genome in the exttacellular enviromnent, the protein subunits of the capsid or nucle-ocapsids have to be transported to the assembly point where they will form the final particles around the viral nucleic acid. If this process does not occur in an orderly and programmed manner, the capsid subunits will not form the required multimers and the viral components will become targets for the cellular disposal mechanisms. 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

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