Researchers at IIT Delhi have developed a new visible-light driven chemical strategy to prepare unnatural amino acids. Unnatural amino acids are powerful tools in modern medicine and biotechnology. Several approved drugs use modified amino acids to enhance therapeutic effects.

New Delhi: Like our left and right hands, some molecules are mirror images that can't perfectly overlap; this property is called chirality, or molecular “handedness.” Living things frequently recognize and react to the two versions of such molecules (enantiomers) quite differently, even though they have the same atoms arranged in the same way. It is this simple difference that is the essence of life. Nature displays a striking preference for one molecular “hand” or ‘enantiomer’ over the other. From the DNA that encodes our genetic information to the sugars that power our cells, chirality is everywhere. Nowhere is this more remarkable than in proteins—the tiny molecular machines that carry out almost all the work inside our bodies.

Proteins are constructed from small building blocks called amino acids. This is where the chirality in proteins comes from. The fact that nature almost exclusively employs one enantiomer of these amino acids is truly remarkable. However, even a minor modification in molecular handedness can significantly alter the behaviour of a protein and alter its shape. For decades scientists have explored whether nature’s limited set of amino acids could be expanded. They aim to create new unnatural amino acid building blocks that can improve protein stability, strength, and functionality.

Unnatural amino acids are powerful tools in modern medicine and biotechnology. They enable the creation of biomimetics that mimic natural proteins while offering improved stability, longer activity, and better target selectivity. Several approved drugs, such as bortezomib, octreotide, and baclofen, use modified amino acids to enhance therapeutic effects. Beyond medicine, they help researchers engineer proteins, study biological processes, and design molecules with new functions. They also serve as building blocks in organic synthesis, catalysis, and the development of advanced biomaterials.

Inspired by the need for more efficient ways to access these valuable building blocks, researchers at IIT Delhi led by Prof. Ravi P. Singh, Department of Chemistry, developed a new strategy for the precise synthesis of unnatural amino acids and peptides.  

“The biggest challenge was to generate a single enantiomer of the amino acid in a selective way, which is important because biological systems usually only recognize one specific three-dimensional configuration of a molecule,” said Prof Singh.  

They have developed a new visible-light driven chemical strategy to prepare unnatural amino acids with precise control of their three-dimensional structure. Light energy and a chiral copper catalyst–ligand system were also utilized by the scientists to control chemical transformations with a high degree of selectivity. The method is based on using simple and readily available natural amino acid building blocks and allows efficient introduction of new chemical groups to generate a diverse set of unnatural amino acids. The major advantage of this approach is that it provides a large repertoire of unnatural amino acids for the design of next-generation biomolecules.  

“With this strategy we could generate 43 examples of UAAs and peptides. Thus, we created building blocks for various unnatural proteins, which can be formed with unlimited possibilities of combining UAAs, opening an entire world of new biological space," Prof. Singh added.

The research has been published in Org Lett. 2026 (https://doi.org/10.1021/acs.orglett.6c02280).

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