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Mar 20, 2014

Technique Reduces Peptide Synthesis to a Matter of Hours

  • A research team at MIT says they have designed a method to make peptides in hours rather than several weeks. The new system, described in a paper (“Rapid Total Synthesis of DARPin pE59 and Barnase”) in ChemBioChem, could have a major impact on peptide drug development, says Bradley Pentelute, Ph.D., an assistant professor of chemistry and leader of the research team.

    “Peptides are ubiquitous. They’re used in therapeutics, they’re found in hydrogels, and they’re used to control drug delivery. They’re also used as biological probes to image cancer and to study processes inside cells,” Dr. Pentelute explains. “Because you can get these really fast now, you can start to do things you couldn’t do before.”

    Therapeutic peptides usually consist of a chain of 30 to 40 amino acids, the building blocks of proteins. Many universities, including MIT, have facilities to manufacture these peptides, but the process usually takes two to six weeks, using machines developed about 20 years ago. These machines require about an hour to perform the chemical reactions needed to add one amino acid to a chain.

    To speed up the process, the MIT team adapted the synthesis reactions so they can be done in a continuous flow system. Using this approach, each amino acid addition takes only a few minutes, and an entire peptide can be assembled in little more than an hour.

    “Leveraging our recently developed fast-flow peptide-synthesis platform, we rapidly explored numerous conditions for the assembly of long polypeptides, and were able to mitigate common side reactions including deletion and aspartimide products,” write the investigators. “We report general strategies for improving the synthetic quality of difficult peptide sequences with our system. High-quality protein fragments produced under optimal synthetic conditions were subjected to convergent native chemical ligation, which afforded native full-length proteins after a final desulfurization step. Both DARPin and Barnase were folded and found to be as active as their recombinant analogues.”

    In future versions, “we think we’re going to be able to do each step in under 30 seconds,” continues Dr. Pentelute, who is also an associate member of the Broad Institute. “What that means is you’re really going to be able to do anything you want in short periods of time.”

    The new system has storage vessels for each of the 20 naturally occurring amino acids, connected to pumps that pull out the correct one. As the amino acids flow toward the chamber where the reaction takes place, they travel through a coil where they are preheated to 60 degrees Celsius, which helps speed up the synthesis reaction.

    “We’re on par with the world’s best state-of-the-art synthesis, but we can do it much faster now,” according to Dr. Pentelute, who adds that with this technology scientists could design and rapidly test new peptides to treat cancer and other diseases, as well as more effective variants of existing peptides, such as insulin.

    Another benefit of this high-speed approach is that any potential problems with a particular peptide synthesis can be detected much sooner, allowing the researchers to try to fix it right away.



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