Author: chemistadmin

The development of molecules to study and treat disease is becoming increasingly burdened by the time and specificity required to analyze the vast amounts of data generated by synthesizing large collections of new molecules. Scientists at St. Jude Children’s Research Hospital present a novel solution to this problem, using the fundamental fragmentation patterns of chemical building blocks to barcode reactions from starting materials to products.

In doing so, they have removed a key bottleneck in the process of synthesizing and screening small molecules. Their work is published in Nature.

Current analytical methods lag the scale of rapid, high-throughput analysis desired by researchers. Scientists at St. Jude, led by Daniel Blair, Ph.D., St. Jude Department of Chemical Biology and Therapeutics, set about solving this problem by capitalizing on a general feature residing in most chemical reactions.

“Generality is essential for doing anything quickly. So, we sought to identify general features which would uniformly encode the analysis of small molecules,” explained Blair, corresponding author of the article.

“We discovered that the building blocks we use to create small molecules break apart in specific, predictable ways and that these patterns can then be used as universal barcodes to analyze chemical products.”

A fragmentation-first approach to experimental design

Fragmentation is a fundamental property of chemical matter, but this novel application in the realm of chemical synthesis is giving it new meaning. A general rate for analyzing a chemical reaction’s outcome is conventionally around 3 minutes, but as researchers scale up, analyzing additional reactions with more variables, that amount of time becomes impractical.

This work by Blair and the team transforms chemical reaction analysis from a slow, highly customized and specialist-driven method to a streamlined approach driven by simple-to-identify fragmentation barcodes and a single analytical readout.

“Because these fragmentation patterns are a fundamental property of chemical matter, they are reliably transposable from starting materials to products. As soon as you recognize that starting materials can define the analysis of the resulting chemical products, you’ve generalized the entire approach,” said first author Maowei Hu, Ph.D., St. Jude Department of Chemical Biology and Therapeutics.

This fragmentation-first approach to high-throughput experimental design can be applied in many ways because this fundamental property is not disease- or discipline-specific. Future applications may include the development of antibiotics, antifungals, cancer therapeutics, molecular glues and many more types of molecules.

“We’ve not only transformed the speed of chemical reaction analysis but also paved the way for directly utilizing these molecules to understand and combat diseases,” said Blair.

“This advance represents a significant milestone in our mission to develop effective therapies swiftly and efficiently. We’ve transformed chemical reaction analysis from minutes to milliseconds, and in doing so, have shifted the bottleneck from making molecules to finding functions.”

How can aromatic compounds be separated from aliphatic compounds efficiently without having to rely on energy-intensive processes? In an article published in the journal Angewandte Chemie International Edition, chemists from Heinrich Heine University Düsseldorf (HHU) present an innovative molecular sieve made of partially fluorinated macrocycles that can separate these compounds selectively.

Aromatic compounds—substances with flat, ring-shaped structures made up of carbon atoms—play an important role in organic chemistry. Among other things, they serve as solvents or feedstock for many plastics and are also used in fuels. One well-known example is benzene (C₆H₆).

Its aliphatic counterparts, such as cyclohexane (C₆H₁₂), are also ring-shaped. However, by contrast with aromatics, they are flexible and thus form a zigzag-like, three-dimensional structure.

Separating aromatics from other organic compounds—in particular aliphatic hydrocarbons—is a major challenge, yet often necessary. For example, cyclohexane is produced by hydrogenation of benzene, resulting in a mixture of both substances.

Separation processes used to date require a significant amount of energy, as the physical properties of the compounds, such as boiling points and vapor pressure, are virtually identical.

The research team headed by HHU chemist Dr. Bernd M. Schmidt (Functional Supramolecular Systems Research Group) and the research group headed by Professor Dr. Christoph Janiak (Chair for Nanoporous and Nanoscale Materials) have together developed a supramolecular sorting machine, which can realize the separation in a different way. It comprises electron-deficient, fluorinated macrocycles with a rectangular structure called squareimines, which predominantly adsorb aromatic molecules.

Schmidt says, “In the squareimines, small, three-dimensional molecules accumulate in the solid body in such a way that the connection of the cavities creates a network of pores.” This ultimately results in a network of many tubes arranged in parallel next to each other, each of which has a diameter of less than one nanometer. “This porous structure, acting as a ‘supramolecular sponge,’ can trap small molecules such as gases or volatile organic compounds,” Schmidt continues.

The researchers optimized the adsorption capability of their material through the targeted, controlled linking of the structures. Tobias Pausch, Ph.D. student in the research group headed by Dr. Schmidt and lead author of the study, states, “The squareimine NDI2F42 has a strong affinity for aromatic compounds such as benzene and toluene, while ignoring their aliphatic counterparts.”

The chemists are already measuring high selectivities of up to 97:3 for benzene over cyclohexane and 93:7 for toluene over methylcyclohexane in initial tests. “This means that almost exclusively aromatic compounds are adsorbed into the crystalline, supramolecular sponge, while the aliphatic compounds are left behind,” says Pausch.

Schmidt claims, “The identified squareimines offer great potential for molecular separation. This is due not only to their favorable structure, but also to their diversity, making it possible to produce tailored sorters for highly specific compounds. They are also easy to produce, making them a promising platform for new, innovative and lightweight adsorber materials.”

Microbial organisms adapted to extreme and inhospitable environments carry proteins within their proteome that significantly accelerate the dissolution of CO₂ in water, while also withstanding very high temperatures and pH. These enzymes are valuable promoters of CO₂ capturing from industrial exhaust streams. Researchers at the Biomedical Sciences Research Center Alexander Fleming (BSRC Fleming) in Vari, Greece, have identified such a bioactive molecule.

Microorganisms producing resilient proteins and enzymes have evolved to thrive in extreme conditions, such as hot springs, salt lakes, and volcanoes. A team of Greek researchers, led by Dr. Georgios Skretas at BSRC Fleming developed new metagenomic analysis tools to identify a super heat-resistant enzyme of biotechnological interest.

After scanning millions of genes from open-access metagenomic databases, a new promising candidate biocatalyst was found in a metagenomic sample originally collected from a hot spring in the Kirishima region of Japan. Through this process, the scientists from the Skretas Lab discovered the highly stable carbonic anhydrase CA-KR1. This robust enzyme specializes in enhancing the dissolution of CO₂ in water and exhibits unprecedented stability under industrial conditions.

“Metagenomic analysis gives us access to a ‘pool of proteins’ that remains largely unexplored and can unravel enzymes and other proteins of great biotechnological interest, such as the CA-KR1 enzyme we have discovered,” comments Dr. Skretas. According to Dr. Skretas, the CA-KR1 enzyme is extremely stable at very high temperatures and in strong alkaline solutions, which is extremely rare for proteins.

“More specifically, the enzyme performs exceptionally well under conditions of Hot Potassium Carbonate (HPC) capture technologies, with temperatures exceeding 80 °C and pH levels above 11. It enhances CO₂ capture productivity by 90% at 90 °C compared to standard non-enzymatic methods. It also allows for 90% CO₂ removal at 80 °C, surpassing the performance of standard HPC capture and doubling the initial CO₂ absorption rate at 90 °C,” explains Ph.D. candidate Konstantinos Rigkos, who, along with the Post-Doctoral Researcher Dimitra Zarafeta, played a central role in this study, recently published in Environmental Science & Technology.

“The CA-KR1 enzyme is perhaps the most robust biocatalyst (carbonic anhydrase) for efficient CO₂ capture in HPC conditions reported to date. Its integration in industrial settings holds great promise for accelerating the industrial implementation of biomimetic CO₂ capture—a green, sustainable technology expected to be a ‘game changer’ in carbon sequestration, significantly contributing to the timely achievement of carbon neutrality,” added Dr. Zarafeta.

The innovative enzyme CA-KR1 is already patent-pending. Its transition from the laboratory bench to the industrial bioreactor will be an important step toward industrial decarbonization, significantly contributing to innovation in the critical area of CO₂ capture for the well-being of the planet. These studies are currently underway.