Scientists have developed a route to better-binding RNA molecules and found a binder for HIV-1 RNA.

Aptamers are short strands of nucleic acid that bind strongly to molecular targets and are important in the fields of biotechnology and therapeutics. Now, Anthony Bugaut and colleagues at the Université Victor Segalen in Bordeaux, France, have combined a step-by-step route to better-binding aptamers with chemical modification to make large libraries of optimised aptamers.

A new route to better-binding RNA molecules.

The small number of nucleic acid building blocks has limited the range of aptamers that can be made, and chemical modification is a way to improve their binding properties. Previously this involved either using modified building blocks (a trial-and-error approach), or functionalising the aptamers after synthesis (requiring detailed knowledge of the aptamer-target interaction), said Bugaut. The new approach eliminates these drawbacks by using an iterative process, called SELEX (systematic evolution of ligands by exponential enrichment), so that only the best aptamers go on to the next round of chemical modification.

In Bugaut's approach, an equilibrium mixture of products is formed from a large library of aptamers (amines) and a limited set of reagents (aldehydes). When the target molecule is added, some of the products bind to it, shifting the amine/aldehyde equilibrium - a process known as dynamic selection. The products that have bound to the target are isolated, and the aldehydes released, giving the improved set of aptamers. The aptamer levels are increased in a process called amplification, and the whole process repeated until only the best aptamers are left.

The team used the method to find an aptamer that binds to a region of HIV-1 that is involved in its replication. The strategy could 'greatly expand the applications of aptamers for diagnostics, therapeutics and nanobiotechnologies,' said Bugaut. 

Eric Westhof, an RNA expert from the Université Louis Pasteur, Strasbourg, France, agreed, adding that the structures of the new aptamers 'could reveal exciting novel paradigms for molecular recognition.'

David Barden