Some highlights from chemical biology of nucleic acids

With the recent developments in antisense oligonucleotide therapy, the need for more stable and easy to synthesize nucleic acid mimics is increasing.

The group of Prof. Holliger (Cambridge, UK) reported on the engeneering a DNA/RNA polymerases that are capable to incorporate unusual 2′-5′ linkages between nucleotides. The practical significance aside, the gels from their recent ACIE paper suggest that the group is on the right track, but not quite there yet. While purine nucleobases can be effectively incorporated into growing DNA/RNA chain, the pyrimidines seem to be more stubborn.

In the meanwhile, Damha lab expands diversity of nucleic acid mimics by introducing seven-membered rings (oxepans) instead of ribose. The work is an extention on their previous paper from 2007. The expansion mainly deals with diastereo- and regioselective functionalization of expanded sugar ring via epoxydation and opening of oxirane cycle. Well, there is certainly more opportunities to stick something into seven-membered ring, than into five-membered one, but utility of these modifications is yet to be demonstrated.

While Damha lab’s work contributes to the exploration of endless conformational landscapes of nucleic acid dynamics, other groups study naturally occurring ones. Methylation of nucleobases is a well-known phenomenon regulating gene expression and general stability of RNA and DNA. It’s not surprising that it affects energetics of base-pairing in a variety of ways: either by introducing sterical clashes or a positive charge into interacting base pairs. What Lee’s group from Austin found, is that N7 methylation of G affects equilibrium between keto and enol tautomers. So it completely reverses hydrogen bond donor/acceptor properties of exocycilc oxygen and nitrogen N1. This leads to Watson-Crick like recognition of dT and change in the preferred geometry of G-A internal loop. Quite a cool stuff!

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Author: Slava Bernat

I did my PhD in medicinal chemistry/chemical biology of G protein-coupled receptors and then explored some chemical biology of non-coding RNA as a postdoc. Currently I'm working in a small biotech company in San-Francisco Bay area as a research chemist. I'm writing about science, which catches my attention in rss feed reader and some random thoughts or tutorials.

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