With its unique capacity for label-free, real-time generation of detailed information on binding interactions, surface plasmon resonance (SPR) has established itself as a mainstay in drug discovery research. Long-time market incumbents and newer SPR instrumentation suppliers alike are addressing the demand for increases in throughput and expanded range of application.
The standard technology involves a chip or cartridge, on which rest immobilized ligands of interest and below which is a prism. A solution is passed over the chip, and light is shone through the prism at a constant angle.
As the assay solution passes over the chip, temporal ligand-target binding events (as well as binding events with nontarget molecules) result in increases in the molecular weight at the binding points. The target (or other) molecule will dissociate from the ligand according to its own dissociation kinetics.
The temporary changes in mass in turn effect shifts in the angle of light refracted through the prism, which is visually recorded in a “sensorgram”. Computer-aided analysis of sensorgrams renders precise quantitative information about the ligand, target, and interactions between them, for applications in protein and DNA interactions, monoclonal antibody identification, drug-lead evaluation, optimizing purification methods, and even drug formulation and production. As always in the bioindustry, throughput is critical.
Throughput, Sensitivity, Accessibility
Yet “the big issue, even with throughput, is the complexity and subsequent bottleneck in assay development. There are few options for simple systems that can both run and develop assays in a high-throughput manner,” says Christopher Whalen, CEO of Sierra Sensors.
“Along with throughput, there has been relatively little in the way of breakthroughs in detection sensitivity such that small molecule analysis can become more routine.”
Sierra Sensors recently acquired an SPR detection technology from Agilent Technologies that Sierra is developing into what it calls SPR+. The SPR+ detection will be the foundation of a new, “higher throughput, high performance” label-free analysis platform dubbed the MASS-1 (Molecular Affinity Screening System), that Sierra Sensors plans to launch in mid-2011.
The MASS-1 will have eight channels and 16 sensors, enabling the simultaneous analysis of eight samples. The SPR+ detection technology will offer 10- to 100-log improvement in the low-end detection sensitivity of SPR, according to Whalen, to allow for analysis of small molecule binding events “in a much more robust manner.”
In the last few years, Sierra Sensors has also demonstrated its Hydrodynamic Isolation™ (HI) continuous flow, microfluidic sample-delivery technology. HI was designed to enable simultaneous addressing of multiple sample solutions to individual locations on a 2-D sensor array, with all samples delivered as discrete volumes in a continuously flowing assay-buffer stream.
With sensitivity and flow-based throughput, label-free analysis (that is, SPR) could then be applied to true secondary screening (as opposed to simply rerunning confirmatory primary screens of initial hits) and tertiary screening.
“Many of our customers would like to do true secondary screens, where they look either at different targets or different parameters of the primary-screen binding event. Secondary screens using label-free technology will permit qualitative and quantitative screening of compounds with detailed kinetics data, such that off-rates could be ranked very early in the screening process,” Whalen notes. “Researchers can then isolate only those compounds that meet their requirements. This is true quantitative screening.”
Accessibility of SPR technology, which has traditionally been quite costly, is also something companies like Sierra Sensors are tackling. “Academic researchers and smaller labs are often looking for basic, desktop instruments and cannot afford the top-of-the-line equipment. They simply want to do benchtop label-free assays cost-effectively and without much difficulty,” says Whalen.
Sierra Systems’ fully automated SPR-2 instrument is designed to address this market, with a two-channel SPR system that provides “high-performance SPR in a low-throughput platform.” For groups focused on analysis of cells, membranes, and crude samples, Sierra offers its QCMA-1 analysis system, based on the company’s quartz crystal microbalance detection technology.