This DNA sequencing method reveals where and how small molecule drugs interact with their target genome



Many life-saving drugs interact directly with DNA to treat diseases such as cancer, but scientists have struggled to uncover how and why they work — until now.

In a paper published in the journal Nature BiotechnologyIn this study, Cambridge University researchers have identified a new DNA sequencing method that can detect where and how small molecule drugs interact with their target genome.

Understanding how medications work in the body is essential to creating better and more effective treatments. But when a therapeutic drug enters a cancer cell with a genome containing three billion bases, it’s like entering a black box.”


Dr.. Zhoutao Yu, co-author, Yusuf Hamid, Department of Chemistry

The powerful method, called Chem-map, lifts the veil of this genomic black box by enabling researchers to discover where on the DNA genome small molecule drugs interact with their targets.

Every year, millions of cancer patients receive treatment with drugs that target the genome, such as doxorubicin. But despite decades of clinical use and research, the molecular way of working with the genome is still not well understood.

“Many life-saving drugs interact directly with DNA to treat diseases such as cancer,” said co-first author Dr. Jochen Spiegel. “Our new method can pinpoint where drugs are attached to the genome, which will help us develop better drugs in the future.”

Chem-map allows researchers to conduct On site mapping the interactions of small molecules with the genome at unprecedented resolution, using a strategy called small molecule-directed Tn5 transposases. This detects a binding site in the genome where a small molecule binds to genomic DNA or DNA-binding proteins.

In the study, the researchers used Chem-map to identify direct binding sites in human leukemia cells for the large-scale anticancer drug doxorubicin. The technique also showed how combined treatment with doxorubicin on cells already exposed to the histone deacetylase (HDAC) inhibitor tucidinostat could have potential clinical advantage.

This technique has also been used to map the binding sites of specific molecules on DNA G-quadruplexes, known as G4s. G4s are four-strand secondary structures involved in gene regulation, and could be potential targets for future anticancer therapies.

“I am very proud that we have solved this long-standing problem – we have created a highly efficient approach that will open many paths for new research,” Yu said.

Professor Sir Shankar Balasubramanian, who led the research, said: “Chemical mapping is a powerful new method for discovering the location in the genome where a small molecule binds to DNA or DNA-binding proteins. It offers tremendous insights into how certain drug therapies interact with the human genome, and make It is easy to develop more effective and safer drug therapies.”

Source:

Journal reference:

yo, z, et al. (2023) Chemical map features drug binding to chromatin in cells. Nature Biotechnology. doi.org/10.1038/s41587-022-01636-0.



Source link

Related Posts

Precaliga