Researchers from the Universidad de Alcalá (UAH) managed by Professor Federico Gago from the pharmacology department, have published an article in the Journal of Medicinal Chemistry clarifying the molecular bases of DNA sequence identification by Thiocoraline A, a marine antibiotic compound with antitumoral action.
This molecule is a product of the biopharmaceutical company PharmaMar (http://www.pharmamar.com/es/pipeline/) and has a potent cytotoxic effect over a wide range of tumour cells both animal and human. The 3D structure of thiocoraline, determined by X-ray crystallography at the Universidad de Santiago de Compostela, shows a characteristic staple shaped pattern that explains its bisintercalative property in the DNA double helix (fig) as well as the particular arrangement of the pairs, piling up in columns inside the crystal structure.
Thanks to this double intercalation, thiocoraline is able to identify specific sequences of DNA and attaches to them, making it harder for the strands of DNA that form the double helix to separate.
In order to evaluate this effect, Professor Alberto Domingo from the biochemistry and molecular biology department of the UAH used tiny quantities of DNA linked to a fluorescent marker and standard instruments for reverse transcription polymerase chain reaction (RT-PCR). The information produced by this miniaturised method, that has proven to be a far superior technique to the those used in the past for this kind of experimentation, shows the binding affinity of thiocoraline for DNA in great detail, and has later been computer modelled for better understanding. In this way, it has been possible to verify that the flat rings of this molecule intertwine with the two closest base pairs while leaving another two pairs in between free in accordance with the exclusion principle; the rest of the molecule establishes hydrogen bonds with the central base pairs.
The resulting complex resembles a sandwich in which the bread is represented by the rings of the agent and the filling is the base pairs trapped by the thiocoraline (fig). It’s mainly these hydrogen bonds that grant the antibiotic the ability to bind selectively and this area is currently still under investigation at PharmaMar, a company of the Zeltia group that was recently granted approval by the Spanish health authorities for a new product of marine origin - the trabectedin (Yondelis) - aimed to treat sarcoma in soft tissues.
Authors: Federico Gago y Ana Negri
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