The overall goal of the research program is to transform the field of aptamer technology.
The progress of the aptamer field has so far been hampered by the relative large size and poor biostability of evolved aptamers composed of unmodified nucleotides necessitating tedious and extensive post-SELEX truncation and modification approaches. LNA is in the process of revolutionizing the antisense field, and it has potential to do the same with aptamer technology. The key for transforming aptamer technology is to directly enable evolution of aptamers that possess most of the desired properties, thereby alleviating the need for most post-SELEX procedures. It is the ambition within EVOLNA to develop LNA aptamer technology to this stage. It is envisioned that de novo evolution of LNA aptamers will allow increased chemical diversity space while at the same time enabling size reduction and increased biostability compared to standard evolved aptamers, and the minimal size attainable by aptamer de novo evolution will be explored. The following points illustrate how LNA will have a very significant impact:
- LNA nucleotides induce an unprecedented propensity towards base pairing when incorporated into DNA or RNA oligonucleotides. This will enable evolution of unique short yet highly structured aptamers.
- LNA nucleotides increase biostability of oligonucleotides by increasing resistance towards exo- and endonucleolytic degradation and by stabilizing formed secondary structures. This will enable evolution of highly biostable aptamers.
- LNA nucleotides can be functionalized as 2’-amino-LNA nucleotides carrying amino acids, peptides etc. without impacting its unique hybridization properties. This will enable straight-forward functionalization and chemical diversity expansion of LNA aptamers.
- LNA nucleotides are expected to effect their high-affinity hybridization also when combined with other aptamer-relevant nucleotides like 2’-fluoro-RNA and 5-substituted pyrimidine nucleotides. This will enable evolution of short yet highly biostable, structured and functionalized aptamers.