Aptamers are DNA or RNA molecules that can bind with high affinity and/or specificity to target molecules. Given their properties, aptamers offer numerous advantages for diagnostic, biodetection and nanotechnology applications. However, aptamers being made of natural nucleic acids suffer from certain limitations. For instance, they are rapidly degraded when directly injected into patients, and their relatively low chemical diversity prevents them from binding to certain targets. Scientists at the Institut Pasteur successfully improved the properties of aptamers by applying techniques that are commonly used in medicinal chemistry..
Aptamers can be thought of as analogs of antibodies that are entirely composed of nucleic acids (DNA or RNA). These structures can form specific complexes with protein targets that offer a wide range of potential applications. But aptamers have several limitations as a result of their natural composition. Introducing chemical modifications is a way of overcoming some of these problems. For the first time, scientists from the Bioorganic Chemistry of Nucleic Acids Unit at the Institut Pasteur, in collaboration with the Crystallography Platform in the Center for Technological Resources and Research (C2RT), used chemical modifications that are entirely absent from living systems but widespread in medicinal chemistry to improve the properties of aptamers.
The example of malaria to improve our understanding of aptamers
"We used a chemical modification known as cubane to isolate aptamers with the ability to bind to a protein used as a biomarker for malaria detection," explains Marcel Hollenstein, Head of the Institut Pasteur's Bioorganic Chemistry of Nucleic Acids Unit. Malaria is spread by a parasite of the genus Plasmodium, which has four human-specific species. Precisely identifying the Plasmodium species, especially P. falciparum (the most virulent) and P. vivax (responsible for subacute, chronic malaria) remains difficult.
"The aptamer that we were able to isolate binds specifically – because of this chemical modification – to the protein in P. vivax used to detect it. We demonstrated that the aptamer can be useful in distinguishing P. vivax from P. falciparum in diagnostic assays mimicking a clinical situation," continues Marcel Hollenstein.
As well as the major potential of this modified aptamer for detecting Plasmodium species, the scientists also demonstrated that introducing this chemical modification enabled the aptamer to interact with proteins in new ways. With a combination of methods from medicinal chemistry and molecular biology, they successfully identified aptamers capable of recognizing Plasmodium species by using new interaction mechanisms. This discovery paves the way for the potential development of new diagnostic tests.
"This approach could be applied more widely to identify aptamers with increased chemical diversity and capable of binding to more challenging targets," concludes Marcel Hollenstein.
Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker, PNAS, 6 juillet 2020
Yee-Wai Cheung1,5, Pascal Röthlisberger2,5, Ariel E. Mechaly3, Patrick Weber3, Fabienne Levi- Acobas2, Young Lo1, Alvin W.C. Wong1, Andrew B. Kinghorn1, Ahmed Haouz3, G. Paul Savage4, Marcel Hollenstein*2, and Julian A. Tanner*1
1 School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
2 Institut Pasteur, Laboratory for Bioorganic Chemistry of Nucleic Acids, Department of Structural Biology and Chemistry, CNRS UMR-3523, 28, rue du Docteur Roux, 75015 Paris, France.
3 Institut Pasteur, Crystallography Platform-C2RT, Department of Structural Biology and Chemistry, CNRS UMR-3528, 25-28 rue du Docteur Roux, 75015, Paris, France.
4 CSIRO Manufacturing, Bayview Avenue, Victoria, 3168, Australia.