New test could aid lab research into anti-cancer drugs
anti-cancer drugs is to be made significantly easier after
scientists developed a litmus test that determines the bonding
strength of DNA, small molecules and proteins to DNA.
The test is primarily aimed at pharmaceutical companies that are always on the lookout for methods to improve hit rates when screening millions of compounds with a view to further development.
What is unique about this test, called colorimetric screening, is the simplicity, with bond strength indicated with a colour change.
The research team used the colorimetric method to screen for molecules that can facilitate the formation of a special form of DNA called a triple helix. Triple helix DNA involves three strands rather than the normal two and is highly unstable requiring a small molecule triplex binder to increase its stability.
"Pharmaceutical companies are targeting DNA for different therapies, and they need to identify DNA or small molecules that selectively bind to DNA to turn on or off the gene expression related to a particular disease," said Chad Mirkin, professor of medicine and professor of materials science and engineering, who led both studies.
"Our method is faster and more convenient than conventional methods and should help researchers zero in on potential anti-cancer agents from their large libraries of candidates more quickly."
Estimates have placed the price of failure at $50-70m (€39-54m) with approximately 90 per cent of clinical candidates failing at development stage
Added to the mass of data generated, which needs to be analysed and interpreted, a tool that can identify compound leads with promising drug development potential, as well as predict biological properties would be warmly received.
In a paper reported online by the Journal of the >American Chemical Society (JACS), the research team demonstrated the phenomenon that occurs when a triplex binder binds to a given DNA triple helix in solution the strength of that binding event can be detected by the naked eye.
The colour of the solution changes from blue to red when heated, and the temperature at which this occurs indicates the strength of the triplex binder's bond.
The researchers started with gold nanoparticles, held together by DNA in a triple helix conformation.
Because they are held together within a certain critical distance, the gold nanoparticles - and the solution they are in - are blue.
When the solution is heated, the DNA breaks apart, and the gold nanoparticles, no longer in close proximity to each other, are now bright red.
"It's impossible to do a full-blown study on every triplex binder or small molecule," said Mirkin.
"You need to narrow down the possible candidates. This method allows researchers to identify the types of triplex binders or molecules that are effective for a given DNA sequence."
Mirkin added that most diseases have a unique genetic code associated with them, and by manipulating the genes with the right triplex binders or small molecules you can develop new therapies.
A certain DNA sequence might be linked to colon cancer, for example, and the proteins expressed by that DNA produce cancer cells.
By identifying a triplex binder or small molecule that binds effectively to that particular DNA sequence, a drug can be developed that shuts down protein production and stops cancer cells from proliferating.
The next step for the team is to challenge the research community to provide libraries of triplex binders and small molecules for his research teams to test. Any interaction with DNA, whether it be with small molecules, proteins or other DNA, can be identified by the colorimetric method.
