Scientists have harnessed essential characteristics of chemical components to significantly speed up the analysis of chemical reactions, reducing the time required from several minutes to mere milliseconds.
As researchers work to create molecules for studying and treating diseases, they often face challenges due to the time and precision needed to sift through the large volumes of data generated from producing new molecules. In a pioneering study, scientists at St. Jude Children’s Research Hospital have introduced a novel method that utilizes the unique fragmentation patterns of chemical building blocks to assign barcodes to reactions, tracing them from initial materials to final products. This innovation addresses a major bottleneck in the processes of synthesizing and screening small molecules. The findings were published today in Nature.
Existing analytical techniques fail to match the rapid, high-throughput analysis that researchers need. A team at St. Jude, led by Daniel Blair, PhD, from the Department of Chemical Biology and Therapeutics, aimed to tackle this challenge by leveraging a common characteristic found in most chemical reactions.
“To work quickly, we knew we needed a general approach. So, we looked for characteristics that could consistently encode the analysis of small molecules,” Blair, the paper’s corresponding author, explained. “We found that the building blocks we use for constructing small molecules tend to break apart in predictable, specific ways, allowing us to use these patterns as universal barcodes for analyzing chemical products.”
A focus on fragmentation in experimental design
Fragmentation is a basic property of chemical substances, and its innovative use in chemical synthesis is providing a fresh perspective. Typically, assessing the outcome of a chemical reaction takes around 3 minutes. However, as researchers increase the scale and add more variables, this duration becomes unmanageable. The work by Blair and his team transforms reaction analysis from a slow and highly tailored method to a more efficient process that relies on easily identifiable fragmentation barcodes and a single analytical output.
“Since these fragmentation patterns are inherent to chemical substances, they can be reliably transferred from initial materials to end products. Recognizing that starting materials dictate the analysis of the resulting products allows us to generalize the entire process,” said Maowei Hu, PhD, the first author from the Department of Chemical Biology and Therapeutics.
This fragmentation-first method for high-throughput experimental design has broad applications since it is not limited to any specific disease or field. Future uses may include the creation of antibiotics, antifungals, cancer treatments, molecular glues, and other types of compounds.
“We have not only accelerated the speed of chemical reaction analysis but have also opened doors for directly using these molecules to study and fight diseases,” Blair stated. “This advancement marks a significant step forward in our goal to develop effective therapies efficiently. We have reduced chemical reaction analysis time from minutes to milliseconds, transitioning the bottleneck from molecule synthesis to function discovery.”
Contributors and funding sources
Alongside Blair and Hu, other authors of the study are Lei Yang, Nathaniel Twarog, Jason Ochoada, Yong Li, Eirinaios Vrettos, Arnaldo X. Torres-Hernandez, James Martinez, Jiya Bhatia, Brandon Young, Jeanine Price, Kevin McGowan, Theresa Nguyen, Zhe Shi, Matthew Anyanwu, Mary Ashley Rimmer, Shea Mercer, Zoran Rankovic, and Anang Shelat, all affiliated with St. Jude.
This research received funding from the National Cancer Institute (R25CA23944), the National Institute of General Medical Sciences (GM132061), and ALSAC, the fundraising and outreach arm of St. Jude.
