June 27, 2006 – In drug discovery work, researchers trying to identify potential new therapies rely on luminescence to identify compounds that interact with a target — that is, a potential new drug. Now a group of researchers at Lumiphore Inc. in Redwood City, Calif., have designed a new type of drug test that can help them discover new compounds at a lower cost than previous methods.
Originally conceived and patented at the University of California at Berkeley by Kenneth Raymond and a group of his students, the technology — what they call a nanoscale flashlight — has pushed the envelope on what is possible, allowing for a broader range of tests with faster results.
“We’re still a spark, about to become a flame,” said Raymond, who moonlights from his post in academia as chairman of the fledgling Lumiphore, which licensed the relevant patents from Berkeley.
High throughput screening technology is constantly trying to expand capacity for testing more samples at a lower concentration and with greater sensitivity. Some drug tests — or assays, as they are known — will test hundreds of thousands, or even millions, of compounds against, to take one example, an enzyme that plays a critical role in a disease. If a compound can modulate the workings of the enzyme, it can possibly play a role in closing the disease pathway that afflicts people. For such assays, researchers rely on luminescent molecules to signal when a compound and the target interact, the first tiny sign of a potential new therapy.
But current technology has been bumping up against its natural limits. For example, a recurring problem is that water molecules can easily deactivate luminescent signals from lanthanides, a group of heavy metals. But Raymond’s crew at Berkeley found they could build a caged complex that shields the lanthanide from water.
“The advantages of using luminescent technology is that you can deal with very low concentrations, and in biology that’s very important,” said Raymond. Some technologies rely on molecules which have very short excited lifetimes. When these molecules are excited, unwanted excitation of plastic materials and other molecules can cause interference and decrease sensitivity. Time resolved luminescence helps deal with that problem by providing a longer period of luminescence.
“The trick there is to have something bright that absorbs light,” Raymond said. “Lanthanides are bad at absorbing light, which is why they’re slow at emitting. You need a molecular component to absorb light. It’s part of what is coordinated to the metal — that’s the ligand. The next part is for the ligand to deliver the energy absorbed efficiently to the lanthanide setting — which is terbium in our case.
“Imagine the ligand as an antenna,” he added. “It absorbs the light energy and goes into an excited state and has a reasonable lifetime in that excited state.”
“The compounds exhibit high brightness and stability in aqueous solutions making them suitable for a variety of applications,” said Todd Corneillie, the head of research and development at Lumiphore. One of the technology’s biggest advantages, he added, is that it allows researchers to run a single-step assay for the results they’re looking for, often avoiding the expensive and time consuming process of multi-step assays.
“Suddenly you can do assays that no one could do before,” said Raymond. Recently Lumiphore announced a deal that allows Echelon Biosciences to use the terbium compounds in assays for PI3-K, a cellular enzyme that is linked to abnormal cell growth in cancer and inflammation. And the company is in talks with other drug discoverers to replicate the Echelon deal with more research pacts.
In addition, Lumiphore has a 50-50 joint venture in the works with Biostride, which also houses its two-man research team, to develop a new approach for detecting frequently abused drugs. The two companies have been developing a diagnostic test which could use the technology to simultaneously test for six commonly abused drugs — a test which could assist police in the field.
Due to lanthanides’ greater sensitivity, Raymond said, the technology is able to use saliva for the field tests, which carries much lower concentrations of drugs than urine. Lumiphore will be looking for approval in Europe and the U.S. on data that is being gathered now and will be submitted to the FDA in a matter of months.