International Business Department           Liu Bojia           October 22, 2024

  In recent years, the emergence of the ‘magic shears’ CRISPR/Cas9 gene editing system has given scientists a revolutionary tool to efficiently rewrite DNA. This was followed by Professor David Liu of Harvard University's single-base editing tool, which allowed precise substitution of individual bases in error without cutting double-stranded DNA.

  Single-atom editing ‘ may be much more unfamiliar to us than single-base editing, but it is an important goal in the field of drug discovery and development. Just as a single base error in DNA can affect traits and even cause fatal diseases, a change in a key atom in an organic compound can determine the efficacy of a drug.

  In drug discovery and development, scientists hope to exploit this ‘single-atom effect’ by altering specific atoms to affect the efficacy of drugs and enhance structural diversity. However, this is not as easy as it sounds, and only a handful of reactions have been able to achieve such substitutions in complex organic molecules. Assessing the drug potency of individual molecules requires tedious and expensive synthesis of all the target structures.

  Recently, a team led by Professor Yoonsu Park at the Korea Advanced Institute of Science and Technology (KAIST) made an important breakthrough when the single-atom editing tool they developed was featured in the journal Science, and a KAIST press release noted that this is the world's first timethat single-atom editing has been achieved under atmospheric pressure at room temperature, providing a new tool to revolutionise the drug discovery process.

  What the study hopes to achieve is ‘backbone editing,’ which is the precise editing of organic molecules by adding, deleting, or altering individual atoms in the core of complex molecular structures. Specifically, the team's goal was to replace one of the oxygen atoms in the five-membered ring of the furan with nitrogen, thereby converting it into a pyrrole backbone that could have a wide range of uses in drug discovery and development.

  Due to the strong chemical stability of the furan's structure, which is ‘aromatic,’ this reaction is not easy to achieve. Previously, the conversion of furan to pyrrole was achieved by high-temperature pyrolysis and high-energy ultraviolet irradiation, respectively, but the former required temperatures as high as 450°C, while the latter yield was too low.

  In their latest study, the team decided to tackle this challenge by means of photocatalysis, and Professor Yoonsu Park described the advantages of this strategy to Academic Jingwei: ‘ Photocatalysis stands out for its precision and its ability to use light energy to perform efficient and mild reactions, minimising harsh conditions and side reactions. This helps to better control the formation of chemical bonds, which is crucial for the development of complex molecules.’

  To do this, the team used acridine-based photocatalysts to absorb low-energy visible light, a process that induces the oxidation of furan to form a positively charged furan radical cation. Compared to furan, this cation is much less stable and is therefore easily adducted by amines ( _R-NH2 ) under mild conditions. As a result, after atomic substitution, the intermediates are reacted by condensation and finally pyrrole is synthesised in high yield.

  As a result, the team has proposed the first strategy for single-atom editing at room temperature and atmospheric pressure, a breakthrough that could simplify chemical synthesis, transform complex molecules and facilitate drug discovery. A companion opinion piece noted that the strategy could be applied to a variety of furan-containing natural products, as well as drugs that use other complex amines, including amino acids and amino sugars, to generate new analogues. This not only demonstrates its compatibility with many functional groups, but also shows its potential for late editing of complex molecules in medicinal chemistry.

  Professor Yoonsu Park looks forward: ‘ The method is expected to be used in drug discovery as it allows selective modification of molecules, giving the opportunity to improve bioavailability or targeting. In addition to furan-to-pyrrole conversion, the photocatalytic approach could be extended to other atom exchange reactions. ’ In the future, the team plans to explore broader applications for the strategy and expand to industrial scale, bridging the gap from laboratory research to drug development.