"Helical, Biomimetic Peptoids as Stable Therapeutic Biomaterials"

Annelise E. Barron
Associate Professor, Department of Chemical and Biological Engineering and
(by courtesy) Departments of Chemistry and of Biomedical Engineering
Northwestern University
Evanston, IL

Recently there has been increasing interest in biomimetic polymer systems that capture some of the advantageous properties of proteins and polypeptides (such as sequence- and length-specificity, and the ability to "fold"), but offer greater stability and more chemical diversity. Poly-N-substituted glycines or peptoids are a particularly interesting class of sequence-specific, peptidomimetic oligomers that are synthesized in our lab by a high-yielding, solid-phase, step-wise protocol -- similar to the way polypeptides are made -- and that are resistant to protease degradation. Sequence-specific peptoids up to about 50 monomers long can be synthesized in good yield, via a submonomer approach, on an automated peptide synthesizer. Oligomers with diverse chemical substituents, including the proteinogenic side chains as well as a virtually limitless number of non-natural chemical moieties, may also be co-polymerized with amino acids to create chimeric oligomers, allowing simultaneous optimization of biomimicry and biostability. Certain peptoid sequences adopt stable, helical structures that resemble polyproline type I helices, such as those found in collagen. Depending on sequence, peptoid helices can be solubilized in either aqueous or organic solution.

We are developing structured polypeptoids as biostable mimics of helical peptides of therapeutic interest. We have synthesized, purified, and characterized helical polypeptoids up to 22 monomers in length, which by virtue of their biomimetic sequences and amphipathic characteristics show good mimicry of the lung surfactant proteins (SP-B and SP-C) and of antimicrobial peptides such as magainin. The development of functional, biostable mimics of surfactant proteins promises to enable the development of a synthetic, biomimetic lung surfactant replacement for safe treatment of respiratory distress. Cationic, facially amphipathic peptoid oligomers that we have designed and synthesized exhibit potent, selective, sequence- and length-dependent antibacterial activity, while being non-toxic to human red blood cells.

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