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Mar 15, 2009 (Vol. 29, No. 6)

Advances in Label-Free Assay Screening

Advantages and Limitations of New Tools Such as RAP, Optical Biosensors, and SPR

  • Optical Biosensors

    Julio Martin, Ph.D., manager of ultra-HTS, molecular discovery research at GlaxoSmithKline, believes that label-free sensors hold promise for filling significant gaps in the drug discovery process. Dr. Martin commented that, while “the explosion of genomics in the 90s was expected to generate an abundant supply of new targets amenable to high-throughput screening assays, the delivery has not lived up to the high expectations.” 

    Dr. Martin imagines a simple technological platform that enables testing any target for hit identification in a similar generic fashion, for instance, through direct binding of compounds to protein. At the same time, the platform should be testing those same compounds in a more complex biological setting that closely resembles the native system, for example in a primary cell line. “This is what label-free can offer,” said Dr. Martin.

    Optical resonance grating sensors in particular, according to Dr. Martin, have proven to be versatile platforms that can detect simple binding events between small compounds and biomolecular targets to complex phenotypic changes in nonengineered cells.

    Optical index of refraction platforms offer a fundamental advantage because they do not require a direct electrical connection between the excitation source, the detection transducer, and the transducer surface (i.e., the sensor). “Optical biosensors and corresponding detectors can be designed to allow measurement of images with resolution of a few microns, that is, an area as small as 1 cm2 can be used to perform several hundred parallel determinations,” he explained.

    Dr. Martin added that “optical biosensors fulfill all the requirements for adoption as a label-free, universal drug discovery platform because they are amenable to high throughput that is rapid, robust, and relatively inexpensive and that can assess large numbers of compounds in a single independent experiment.”

    Serial G-protein coupled receptor activation, Dr. Martin said, is particularly suited to optical label-free assay because G-proteins constitute the most abundant target class for current drug therapeutics and attract a significant part of the drug discovery efforts in pharma. Both native cells expressing endogenous GPCRs and cells overexpressing one particular receptor have been monitored by optical grating sensors in response.

    “Distinct temporal fingerprints are exhibited,” he continued “that seem to be characteristic of the particular receptor coupling pathways triggered by each ligand on a determined cellular background. Optical label-free assays allow the possibility of studying agonist trafficking in any cellular background, including native primary cells, without additional experimental complications other than cell handling. The key is having a strategy and tools to deconvolute the combination of signatures. Deciphering the signature encrypted in a temporal response may be the Rosetta stone of cellular label-free.”

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