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BIOLOGICAL SCIENCES / APPLIED BIOLOGICAL SCIENCES
Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides
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Departments of *Chemical and Biological Engineering and Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208; ¶Biological Nanostructures Facility, Molecular Foundry, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720; and Division of Physics, Department of Biological, Chemical, and Physical Sciences, Illinois Institute of Technology, 3101 South Dearborn Street, Chicago, IL 60616
Edited by Lewis T. Williams, Five Prime Therapeutics, Emeryville, CA, and approved December 18, 2007 (received for review August 31, 2007)
Antimicrobial peptides (AMPs) and their mimics are emerging as promising antibiotic agents. We present a library of "ampetoids" (antimicrobial peptoid oligomers) with helical structures and biomimetic sequences, several members of which have low-micromolar antimicrobial activities, similar to cationic AMPs like pexiganan. Broad-spectrum activity against six clinically relevant BSL2 pathogens is also shown. This comprehensive structure–activity relationship study, including circular dichroism spectroscopy, minimum inhibitory concentration assays, hemolysis and mammalian cell toxicity studies, and specular x-ray reflectivity measurements shows that the in vitro activities of ampetoids are strikingly similar to those of AMPs themselves, suggesting a strong mechanistic analogy. The ampetoids' antibacterial activity, coupled with their low cytotoxicity against mammalian cells, make them a promising class of antimicrobials for biomedical applications. Peptoids are biostable, with a protease-resistant N-substituted glycine backbone, and their sequences are highly tunable, because an extensive diversity of side chains can be incorporated via facile solid-phase synthesis. Our findings add to the growing evidence that nonnatural foldamers will emerge as an important class of therapeutics.
antibiotics | peptidomimetics | structure–activity studies
Present address: Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708254105/DC1.
||To whom correspondence should be sent at the present address: Department of Bioengineering, Stanford University, W300B James H. Clark Center, 318 Campus Drive, Stanford, CA 94305. E-mail: aebarron{at}stanford.edu
© 2008 by The National Academy of Sciences of the USA
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