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Nov 15, 2009 (Vol. 29, No. 20)

Strategies for Companies Targeting GPCRs

Emerging Tools and Methodologies for Screening and Discovery Are Improving Odds for Success

  • In the organism, communication occurs at both the macro and the micro level. At the micro level—inside the cell—communication occurs between proteins relaying messages along signal-transduction pathways from both the internal and external to various compartments within the cell through the process of signal transduction. GPCRs are at the center of many signal-transduction pathways, and as a result, they are the subject of many basic biological research studies, as well as prime drug targets.

    Historically, much of the pharmaceutical industry was only interested in discovering agonists or antagonists when it came to GPCR targets. Currently, however, the industry realizes that there are many more opportunities for targeting GPCRs if it screens for modulators as well as G-protein-dependent and G-protein-independent pathways.

    Investigators are exploring a number of approaches, tools, and technologies related to GPCR drug discovery, and several scientists discussed their research in this area at the Cambridge Healthtech Discovery on Target conference “GPCR-Based Drug Discovery”, which was held in Boston earlier this month.

  • Structural Studies

    Click Image To Enlarge +
    G-protein dependent and G-protein independent pathway activation of activated GPCR (DiscoveRx)

    Fiona H. Marshall, Ph.D., CSO of Heptares Therapeutics, spoke at the meeting about StaR—a thermostable GPCR locked into a chosen conformation by targeted mutagenesis. “GPCR drug discovery is hindered by the need to assay these receptors in cell membranes. This fact restricts the use of modern techniques in drug discovery such as biophysical and structural approaches.”

    By introducing point mutations into GPCRs, Heptares has produced receptors that can be purified like soluble proteins, thus preparing them for biophysical analysis using methods such as SPR, NMR techniques, and x-ray crystallography.

    “This approach enables fragment screening and structure-based design methods to discover drugs for previously intractable receptors.” In addition, other biophysical methods can be used to directly evaluate the biology of ligand-receptor interactions in native cell preparations (e.g., optical biosensors to measure intracellular mass redistributions or cellular dielectric spectroscopy to measure cell surface interactions).

    GPCR-based drug discovery efforts at Heptares include a wide range of targets. In a discovery program targeted at the adenosine A2a receptor for Parkinson’s disease, Heptares has identified a lead compound series (and an unrelated backup series) with, among other pharmacologic properties, potent oral activity in rodent models of Parkinson’s disease.

    Great as structure-based drug design programs may be, there is still a need for drug-screening platforms. DiscoveRx is battling the challenges of GPCR drug research using its screening platforms, which are based on its ß-galactosidase enzyme fragment complementation (EFC) technology.


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