Azane - 22-2-2015 at 11:06
So the discovery and synthesis of PNA is relatively old news by now, but I still have some questions about its structure. Its backbone consists of
alternating glycine and ethane-1,2-diamine residues, and the nucleobases are linked to this backbone by more glycine residues attached to the amino
groups of the backbone's respective glycine residues. Is there any particular reason it was made like this, as opposed to simply using a polyserine
backbone, with the bases linked to the serine's free hydroxyl groups? My only idea is that the glycine and ethane-1,2-diamine residues of PNA's
backbone respectively act as stand-ins of sorts for the phosphate and carbohydrate residues of DNA and RNA. This, I suppose, would keep the polymer's
structure from being too sterically crowded (with nucleobases), as it might be in a polymer that used only serine. Does that sound right?
Dr.Bob - 27-2-2015 at 20:48
The length of the backbone is critical, so the spacing of the linker is key. Efforts have been made to change the spacers, the side linker, the
bases, and even to make the spacer chiral. None of the changed compounds appears to be greatly better, but there are some changes that are slightly
better. The exact spacer is not as critical as the length and geometry of the base (angle from the backbone). The PNA chemistry is pretty well
established, so you would have to have a simpler (or cheaper, faster, or better) chemistry than the current backbone to really make an improvement.
But that is the type of question that a good scientist asks.
Also constraining the side group more, adding a charge to the polymer (positive is good, negative is bad for DNA binding, not surprisingly.), trying
to improve solubility, or improving the DNA pattern recognition selectivity are all good goals. Sadly a great deal of early work on that area was
originally done by one or two pharma companies that never published the bulk of the results, which would have simplified the later work. There was
also a great deal of work done on other antisense DNA/RNA analogs, some of which has made it to the clinic. Most did not. The biggest challenge
was getting the large molecules into cells, where the target of their binding exists.
You could potentially use poly serine, if you only substituted every other serine with a base, it might work. There have been at least a few surveys
of variations on these, none have been substantially better than the achiral original PNA, which is liked precisely due to the simplicity of being
achiral (easier to make and purify). Another advantage of the unnatural PNAs is that they are very stable to enzymes that cleave natural peptides,
compared to just making "natural" peptides. But a simple poly-glycine based PNA with a base off linked off every other glycine unit was made and
found to have very poor DNA binding compared to the original PNA, both with and without an amide in the side chain (unpublished results). I think
that has long since been reported by other groups.
One open access review is quite good:
"Chiral Peptide Nucleic Acids with a Substituent in the N-(2-Aminoethy)glycine Backbone"
Toru Sugiyama 1,* and Atsushi Kittaka 2 - Molecules 2013, 18, 287-310;oi:10.3390/molecules18010287
Another good example is "Chiral peptide nucleic acid monomers (PNAM) with modified backbones" by
Alan Roy Katritzky*a and Tamari Narindoshvilia - Org. Biomol. Chem., 2008,6, 3171-3176,
DOI: 10.1039/B806141F - http://www.ark.chem.ufl.edu/Published_Papers/PDF/1458.pdf
Google "peptide nucleic acids chiral" to get links to a few more of these papers.