UCLA Develops SEE-CITE Technology to Enhance Precision in Drug Discovery and Protein Binding Analysis
核心洞察
UCLA researchers led by Professor Keriann Backus have developed SEE-CITE, a new technology that makes light-activated protein labeling more precise and reliable for drug discovery applications.
The technology enables direct comparison of how different molecules compete for the same protein binding site in a single experiment, addressing longstanding challenges with photo-crosslinking methods.
As proof of concept, the team analyzed cancer (搜索) drugs dasatinib and ascinimib (搜索), revealing that the newer drug ascinimib showed fewer off-target kinase (搜索) interactions.
A UCLA-led international research collaboration has unveiled SEE-CITE, a breakthrough technology that significantly improves the precision and reliability of protein-drug interaction mapping, potentially accelerating drug discovery across multiple therapeutic areas. The innovation, published in Nature Chemistry, addresses a fundamental challenge in pharmaceutical research by enabling scientists to better understand exactly where small molecules bind to proteins.
Revolutionary Approach to Photo-Crosslinking
The new technology builds upon photo-crosslinking, a laboratory method first introduced in 1969 that attaches chemical tags to molecules. When exposed to UV light, these tags lock in place wherever they land on a protein. However, a longstanding limitation has been that chemical tags left behind after UV crosslinking are structurally inconsistent between different molecules, making reliable comparisons impossible.
SEE-CITE solves this problem by giving the molecule being studied the ability to detach from its payload, ensuring each tagged molecule leaves behind a consistent chemical signature. This breakthrough enables quantitative measurements and direct comparisons of how strongly different molecules engage a given binding site, all within a single experiment.
Validation with Cancer Drug Analysis
To demonstrate the technology's capabilities, the research team analyzed the activity of dasatinib and ascinimib (搜索), two cancer (搜索) drugs that target different sites on the same protein—a kinase (搜索) enzyme that causes leukemia (搜索) when mutated. The results not only confirmed known interactions for each drug but also revealed previously unknown interactions.
Significantly, ascinimib (搜索), the newer drug with a more favorable safety profile and fewer side effects, showed fewer off-target kinase (搜索) interactions compared to dasatinib. This finding demonstrates SEE-CITE's potential for evaluating drug selectivity and predicting side effects during the development process.
Broad Therapeutic Applications
The technology's impact extends far beyond cancer (搜索) research. SEE-CITE has potential applications in drug discovery for cholesterol regulation, metabolic liver disorders (搜索), and other therapeutic areas where precise protein-drug interaction mapping is crucial. The method may enable scientists to identify new therapies, reveal previously unrecognized biological activity of existing compounds, and characterize detailed mechanisms of drug-target interactions.
Multi-Institutional Collaboration
The study represents a collaborative effort involving several departments at UCLA, the University of Michigan, research institutes in Spain, and the Japan-based biopharmaceutical company Daiichi Sankyo. The corresponding authors are Keriann Backus, an associate professor of biological chemistry at the David Geffen School of Medicine at UCLA, and Sho Takechi, a former visiting postdoctoral researcher affiliated with Daiichi Sankyo.
The first authors include Chau Ngo, a postdoctoral teacher-scholar in UCLA's chemistry and biochemistry department and the 2023-2024 Donald J. Cram Teacher-Scholar, and Sho Takechi. The technology is covered by a patent application filed by the UCLA Technology Development Group.
Enhanced Data Analysis Capabilities
Beyond the core technology, the research team also upgraded widely used software tools to better interpret the complex data that SEE-CITE generates. This computational enhancement ensures that researchers can fully leverage the technology's capabilities for comprehensive protein interaction profiling.
For the UCLA research group, SEE-CITE represents another significant step in their mission to develop technologies that enable scientists to comprehensively profile all interactions underlying health and disease, potentially transforming how pharmaceutical companies approach drug discovery and development.