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A linguistic model for the rational design of antimicrobial peptides

Nature volume 443, pages 867869 (19 October 2006) | Download Citation



Antimicrobial peptides (AmPs) are small proteins that are used by the innate immune system to combat bacterial infection in multicellular eukaryotes1. There is mounting evidence that these peptides are less susceptible to bacterial resistance than traditional antibiotics and could form the basis for a new class of therapeutic agents2. Here we report the rational design of new AmPs that show limited homology to naturally occurring proteins but have strong bacteriostatic activity against several species of bacteria, including Staphylococcus aureus and Bacillus anthracis. These peptides were designed using a linguistic model of natural AmPs: we treated the amino-acid sequences of natural AmPs as a formal language and built a set of regular grammars to describe this language. We used this set of grammars to create new, unnatural AmP sequences. Our peptides conform to the formal syntax of natural antimicrobial peptides but populate a previously unexplored region of protein sequence space.

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The authors would like to thank M. Zasloff, K. D. Wittrup, R. Berwick, and G. Georgiou for valuable input on the draft manuscript, and J. Moxley for figure preparation. The authors gratefully acknowledge the support of the Singapore-MIT Alliance, the NIH, and the Fannie and John Hertz Foundation.

Author information

Author notes

    • Christopher Loose
    •  & Kyle Jensen

    These authors contributed equally to this work.


  1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Christopher Loose
    • , Kyle Jensen
    • , Isidore Rigoutsos
    •  & Gregory Stephanopoulos
  2. Harvard–MIT Health Sciences and Technology, Cambridge, Massachusetts 02139, USA

    • Kyle Jensen
  3. Agrivida, 411 Massachusetts Ave B1, Cambridge, Massachusetts 02139, USA

    • Kyle Jensen
  4. IBM Research Division, Thomas J.Watson Research Center, Yorktown Heights, New York 10598, USA

    • Isidore Rigoutsos


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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Gregory Stephanopoulos.

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    Supplementary Notes

    This file contains Supplementary Tables 1–3, Supplementary Figure 1 and Supplementary Methods

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