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DNA and RNA as therapeutic targets

 

Nucleic acids are potential therapeutic targets of great interest. First taking advantage of the molecular recognition properties of nucleic acids to selectively inhibit gene expression has been a goal pursued for a long time, first, through the antisense strategies and, more recently, through RNA interference. As we become more aware of the vast number of essential functions carried out by RNA molecules in the cell, these molecules become more attractive targets for the discovery of new therapeutic agents. We are currently carrying out several studies on the interaction of RNA molecules with small ligands of potential therapeutical value.

 

Nucleic acids with chemical modifications

 

Nucleic acids undergo chemical modifications. Sometimes these modifications are related to a particular biological function (DNA methylation, tRNA modification, etc.), in other occasions, these modifications are lesions that must be repaired. Thanks to the new developments in synthetic methods, it is possible to introduce an increasing number of chemical modifications in nucleic acids which allow the artificial modulation of their properties.

In close collaboration with synthetic chemistry groups, we are interested in studying the effect of several modification on the structure and dynamics of nucleic acids.

Some of these modifications are intended to facilitate structural studies by NMR (cyclic oligonucleotides or cross-linked oligonucleotides) and others have a pharmacological interest because they stabilize triple helices or DNA-RNA hybrids. We have also carried out structural studies of modified DNA as models of natural lesions.

 

Non-canonical DNA structures

 

Non-canonical DNA structures, different from the classical double helix, have long attracted scientist attention. Among the different families of non-canonical structures, quadruplexes are of particular relevance since they are potentially involved in important biological processes such as telomere formation, genetic instability by the so-called expansion of triplet-repeats, etc. Moreover, it has recently been suggested that quadruplexes are involved in gene regulation process both at DNA and RNA level.

There are several different types of four-stranded structures. The best known is that formed by guanine tetrads. Another quadruplex motif is the i-motif, formed by intercalated C+C base pairs. The third structural motif is formed by the so-calledminor groove tetrads, formed by the association of two Watson-Crick based pairs through their minor groove side. This association gives rise to four-stranded structures whose topology differs from that of the classical guanine-quadruplexes. In the last few years, our group has devoted a considerable effort to the study of this unusual and less characterized DNA motif.


Other non-canonical structure that we have studied is
the triple helix (or triplex). These structures have pharmacological interest since triple helix formation can block transcription. Triplex formation is highly selective and, in principle, this strategy permits the design of drugs that block the expression of a single particular gene. One current challenge of this strategy is the need to further stabilize the triplex through the appropriated chemical modifications (see the section on nucleic acids with chemical modifications).

 

Interaction with proteins and small ligands

 

 

Nucleic acids are not isolated in the cell, but form complex interaction networks with other biomolecules. Mapping these interaction networks is essential to understand many biological processes. Our group is interested in studying protein-nucleic acids molecular recognition processes. We are involved in a number of structural studies of protein-DNA complexes, protein mimetics of DNA, ribonucleases, etc. Of special interest are our studies of peptides with a very simple composition, able to recognize RNA and that, due to their particularly simple aminoacid composition, might have been present in a prebiotic environment.