Simulation tools drive a new generation of therapies based on gene silencing
Proteins are large and complex molecules which perform different essential functions in the body and they are formed following instructions that are encoded in the DNA. When they read the letters of their DNA, cells produce an intermediate ARN molecule which gives rise to a particular protein. Most diseases are characterized by altered protein levels, which are either the cause or the result of the same condition. In this context, the RNA plays a fundamental role in those diseases with altered protein levels, since it acts as an intermediate messenger between the DNA and the protein.
Proteins are large and complex molecules which perform different essential functions in the body and they are formed following instructions that are encoded in the DNA. When they read the letters of their DNA, cells produce an intermediate ARN molecule which gives rise to a particular protein. Most diseases are characterized by altered protein levels, which are either the cause or the result of the same condition. In this context, the RNA plays a fundamental role in those diseases with altered protein levels, since it acts as an intermediate messenger between the DNA and the protein.
Over the past few years, in order to treat several diseases, research aimed at blocking protein production by RNA has intensified. Now, a study published in the journal Nucleic Acids Research has conducted computational and experimental analyses to produce predictive models that can determine the structure, stability, flexibility and biology of RNA-targeted drugs. The study has been led by Modesto Orozco, professor at the Faculty of Chemistry of the University of Barcelona and head of the Molecular Modeling and Bioinformatics Laboratory at the Institute of Research in Biochemistry of Barcelona (IRB Barcelona) —located in the Barcelona Science Park (PCB)— in collaboration with the biotechnological company Nostrum Biodiscovery.
The experimental research part was carried out in the Experimental Bioinformatics laboratory, led by expert Isabelle Brun-Heath, at IRB Barcelona. The analyses were conducted in collaboration with international biotechnological companies —Biogen and Ionis Pharmaceuticals— as well as the Department of Inorganic and Organic Chemistry of the Faculty of Chemistry of the UB, the Institute of Biomedicine of the UB (IBUB), and the Institute of Physical Chemistry Rocasolano from the Spanish National Research Council (CSIC) in Madrid.
“The project aims to establish the guidelines for developing optimal oligonucleotides to target this intermediate step in, potentially, any protein production process. We now know some of the specific modifications these molecules must undergo to improve thermostability, specificity, and sensitivity to degradation by cellular mechanisms”, notes Orozco, professor at the UB Department of Biochemistry and Biomedicine.
"The simulation tools we have developed are an example of precision engineering since we have systematically looked at every possible modification in every position of the candidate molecules in order to amplify its function. This work has only been possible thanks to the technology available at Nostrum Biodiscovery and the key collaboration of first-class partners, such as Biogen and Ionis Pharmaceuticals”, says Vito Genna, former postdoctoral researcher at IRB Barcelona and now Director of the Nucleic Acids Department at Nostrum Biodiscovery.
To date, the research on these oligonucleotides has been entirely experimental. Now, the biotech company will continue to develop these predictors to build a machine-learning tool that will guide researchers working on these types of therapies and save them time and money.