“Allosteric modulators are regulatory molecules that do not bind to the same site as the receptor’s natural ligand, but rather to alternative sites on the protein, modulating the binding and signaling of the natural ligand,” explains Patricia McDonald, Ph.D., associate director at the Scripps Research Institute. This characteristic offers unique opportunities for the development of a new class of molecular pharmacological agents.
Dr. McDonald and her team focus on the GPCR family of transmembrane spanning receptors that transmit signals from outside the cell to inside the cell through interactions with their cognate G proteins. They are activated by a diverse array of ligands that include light, odorants, hormones, and neurotransmitters. They are noted for their participation in many disease processes, making them important candidates for drug development.
Dr. McDonald has studied arrestin, which binds to activated receptors in a phosphorylation-dependent manner. Arrestin binding to the receptor blocks further G protein mediated signaling, terminating the signal, and desensitizing the receptor, an important regulatory process that prevents the cell from overstimulation.
“The CellKey System is a cell-based label-free technology that measures changes in cellular impedance (Z) using cellular dielectric spectroscopy (CDS),” Dr. McDonald explains.
CellKey measures the integrated response of the cell to receptor activation, permitting interrogation of the mechanism of action of candidate compounds. Following receptor activation, changes in cell morphology, cell adherence, and cell-to-cell interactions contribute to changes in Z. Using this technology the team has developed a strategy to monitor the efficacies of drugs on both receptor activation and desensitization in real time.
“We can detect complex receptor behavior in response to multiple classes of pharmacological agents including allosteric modulators and evaluate their potential therapeutic effectiveness providing valuable insight into how these agents may behave in vivo,” Dr. McDonald says.
Thomas Briese, Ph.D., associate director of the Center for Infection and Immunity and a faculty member at Columbia University, says that the center builds on a bioinformatics approach for sequence analysis and data evaluation, and employs MassTag multiplex PCR, GreeneChip cDNA microarrays, and next-generation sequencing to build an overall picture of the universe of pathogens that threaten global health.
Investigators from the center have created sequence analysis algorithms that deliver automated retrieval, filtering, and alignment of sequences from databases. The goals of the program include characterization of microflora, investigation of outbreaks and pathogenesis of chronic diseases, design and construct field systems for on-site deployment in the developing world, and assessment of animals for potential human-risk agents.
The need for such efforts was amply demonstrated by the West Nile outbreak in New York in 1999, the 2003 SARS outbreak, and more recently, in a nosocomial hemorrhagic fever cluster caused by the Lujo virus.