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A Better Way to Make Unnatural Amino Acids Discovered by Yu

June 26, 2014
Certain amino acids that are not found in nature are highly sought after by pharmaceutical manufacturers. These “unnatural” amino acids have traditionally been very difficult to synthesize, so a new and improved technique for doing so is attracting a lot of attention.

Amino acids are among the most basic components of living things. Long chains of them, translated from DNA, fold up to become proteins, some smaller groupings of amino acids form hormones, and a few single amino acids function as signal-carrying neurotransmitters in the brain. Just twenty-one different amino acids are found in human proteins, and only a handful of others have significant roles outside protein-making. In all, several hundred natural amino acids have been catalogued in living organisms. Yet thousands more are theoretically possible, and researchers expect that many of these “unnatural” amino acids will be medically useful. “This new technique offers a very quick way to prepare drug candidates or building blocks for peptide drugs,” explains Jin-Quan Yu, chemistry professor at The Scripps Research Institute (TSRI), whose team has process in the journal Science (Vol. 343, page 6176, 2014).

In addition to the immense potential structural diversity of unnatural amino acids, many of them are resistant to the housekeeping enzymes that break down and recycle natural amino acids in cells, and thus should last longer in the body. Proposed applications include anti-cancer drugs, antibiotics that are not susceptible to bacterial resistance, and drugs that inhibit the formation of amyloid aggregates seen in Alzheimer’s, Parkinson’s and other diseases.

An unnatural amino acid can be made by taking a natural amino acid – or a closely related molecule – and chemically modifying it. Over the past decade, chemists have developed better and better methods for modifying natural amino acids to make unnatural amino acids, but it involves the breaking of very tough carbon-hydrogen bonds, and major obstacles have remained.

Yu’s group have found a significantly easier method for making this type of modification.

The new method uses special ligand compounds, derived from the simple organic chemicals pyridine and quinolone to enhance the ability of a standard palladium catalyst to break the carbon-hydrogen bonds. The team used the approach to cut two tough bonds in the desired sequence and aryl molecules. Alternatively, the scientists could use the quinoline to attach a common molecule known as an olefin. In both cases they achieved the feat more quickly and simply than had ever been done before. “Many carbon-hydrogen activation reactions that were once out of reach are now possible with these new ligands,” said Yu. Based on detailed studies of how the pyridine and quinoline ligands accelerate these reactions, Yu’s group is already working with second-generation ligands and faster reactions.

Yu’s laboratory is part of a collaboration agreement between TSRI and the pharmaceutical giant Bristol-Myers Squibb. “Under this agreement we are putting the new methods to work to discover novel drug candidates,” Yu said. “In general, we expect that these new developments will greatly expand the scope of research on unnatural amino acids as potential drugs or drug building-blocks.”