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Mimicking Bioactive Peptides with Sequence-Specific Peptoid Foldamers

Annelise E. Barron, Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208

There is growing interest in biomimetic polymer systems with sequence- and length-specificity and an ability to fold into ordered three-dimensional conformations, and which offer greater in vivo stability and/or greater chemical diversity than natural polypeptides. Toward this end we are studying and developing poly-N-substituted glycines, or peptoids, as sequence-specific peptidomimetic oligomers that can be synthesized by a high-yielding, solid-phase protocol – similar to the way polypeptides are made – and which resist protease degradation. Sequence-specific peptoids up to about 45 monomers long can be synthesized in good yield via a “sub-monomer” approach that utilizes primary amines to install the side chain functionalities. Oligomers with diverse chemical substituents, including close cousins of the proteinogenic side chains as well as a virtually limitless variety of non-natural chemical moieties, may also be co-oligomerized with amino acids to create chimeric molecules, 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; we have discovered another set of sequences that adopts an unusual “threaded loop” structure in acetonitrile. Recently we have focused on developing structured polypeptoids as biostable mimics of helical peptides of therapeutic interest. We have synthesized, purified, and characterized helical polypeptoids up to 25 monomers in length, which by virtue of their biomimetic sequences and amphipathic structures show excellent mimicry of the lung surfactant proteins (SP) and of antimicrobial peptides such as magainin. The development of functional, biostable SP mimics promises to enable the development of a synthetic, biomimetic lung surfactant replacement for safe treatment of respiratory distress syndrome in premature infants, and which can be used as a vehicle for pulmonary drug delivery in children and adults. Cationic, facially amphipathic peptoid oligomers that we have designed and synthesized exhibit potent, selective, sequence- and length-dependent antibacterial activity, but are non-toxic to human red blood cells and NIH-3T3 epithelial cells.