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A linguistic model for the rational design of antimicrobial peptides


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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Figure 1: A schematic of the in silico peptide design strategy.


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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.

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Correspondence to Gregory Stephanopoulos.

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This file contains Supplementary Tables 1–3, Supplementary Figure 1 and Supplementary Methods (PDF 176 kb)

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Loose, C., Jensen, K., Rigoutsos, I. et al. A linguistic model for the rational design of antimicrobial peptides. Nature 443, 867–869 (2006).

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