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Breakthrough in Biohybrid Molecules: A New Era of Precision Drug Design

Thanks to an unexpected discovery and extensive research, scientists have now developed methodologies for constructing biohybrid molecules that amalgamate the targeting features of DNA with the diverse functionalities of proteins. This innovation allows for the generation of extensive libraries of potentially therapeutic DNA-protein hybrid molecules, bypassing the traditional one-by-one synthesis method typically employed in chemical laboratories.

The findings from this research have been published in the journal Nature Chemical Biology.

Integration of Nucleic Acids and Proteins

“Nucleic acids—crucial for RNA and DNA construction—and amino acids, which are the building blocks of proteins, are two fundamental components of biological systems,” explained biochemistry professor Satish Nair from the University of Illinois Urbana-Champaign, who spearheaded the study alongside postdoctoral researcher Zeng-Fei Pei. “For many years, chemists have endeavored to fuse these two distinct molecular sets. The ability to fabricate a complex protein and then attach a nucleic acid that directs it precisely to specific DNA or RNA regions opens the door to creating targeted therapies.”

Such therapeutics could be instrumental in disrupting various disease-related cellular processes. For instance, they could prevent the transcription of mutant genes or bind to harmful noncoding RNAs, effectively curtailing their activity, according to Nair.

Serendipitous Discovery and Collaboration

The initial breakthrough was somewhat accidental. Nair and his team were investigating proteins that interact with metals when they stumbled upon an intriguing report from the John Innes Centre in Norwich, England. This report described a molecule produced by bacteria that appeared to be a hybrid of DNA and protein.

After reaching out to the scientists at the Innes Centre—Natalia Vior and Andrew Truman—to re-evaluate the molecule, their collaboration confirmed that it indeed possessed the properties of a DNA-protein hybrid. Following this confirmation, the American and British researchers teamed up to delve deeper into the molecular mechanisms responsible for its formation.

Streamlining the Synthesis Process

The discovery of a naturally occurring DNA-protein hybrid and the methods for inducing its production in bacteria represents a significant advancement. This could potentially expedite a currently slow and labor-intensive biosynthesis process, Nair highlighted.

“Laboratories globally have been employing various synthetic chemical methods to create biohybrid molecules, which has led to numerous successful proof-of-concept studies,” he noted. “However, these methods are not scalable—for instance, producing 100 million compounds would necessitate 100 million separate synthesis efforts.”

Bacterial Enzymes at Work

Through a series of rigorous experiments, Nair and his team identified two bacterial enzymes capable of transforming specific peptides into DNA-protein hybrids. The first enzyme, YcaO, modifies an amino acid within the peptide to form a ring structure akin to the bases that facilitate the pairing of DNA and RNA. The second enzyme, a protease, cleaves a segment of the modified molecule, converting it into a fully active nucleobase-protein hybrid.

The researchers successfully demonstrated this conversion in a test tube using only three components: the original peptide, YcaO, and the protease. They also verified the feasibility of this process within the bacterium E. coli.

This newfound understanding of the synthesis process will empower laboratories to design hybrid molecules capable of binding to specific regions of the genome or RNA in cellular environments, thereby accelerating the pace of scientific discovery.

“We’re now on the fast track to further advancements,” Nair stated enthusiastically.

This significant research was supported by the National Institutes of Health and the Biotechnology and Biological Research Council. In addition to his role as a biochemistry professor, Nair is affiliated with the Department of Chemistry and the Carl R. Woese Institute for Genomic Biology at the University of Illinois.

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