No abstract

Peptoids, oligomers ofN-substituted glycines, are described as a motif for the generation ofchemically diverse libraries of novel molecules. Ramachandran-type plots were calculated and indicate a greater diversity of conformational states available for peptoids than for peptides. The monomers incorporate t-butyl-based side-chain and 9-fluorenylmethoxycarbonyl a-amine protection. The controlled oligomerization of the peptoid monomers was performed manually and robotically with in situ activation by either benzotriazol-lyloxytris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(pyrrolidino)phosphonium hexafluorophosphate. Other steps were identical to peptide synthesis using a-(9-fluorenylmethoxycarbonyl)amino acids. A total of 15 monomers and 10 oligomers (peptoids) are described. Preliminary data are presented on the stability of a representative oligopeptoid to enzymatic hydrolysis. Peptoid versions of peptide ligands of three biological systems (bovine pancreatic a-amylase, hepatitis A virus 3C proteinase, and human immunodeficiency virus transactivator-responsive element RNA) were found with affinities comparable to those of the corresponding peptides. The potential use of libraries of these compounds in receptor-or enzyme-based assays is discussed.Broad screening of compound libraries, of broths grown from soil samples, and of synthetic intermediates has been a fruitful method for discovery of lead compounds in pharmaceutical and agrochemical research (e.g., ref. 1). With the advent of automated chemical methods for solid-phase peptide and nucleotide synthesis, and of molecular biological methods for protein and nucleic acid synthesis, the stage has been set for the generation of new kinds of compound libraries, namely, collections of oligomeric biomolecules (2-14). Such libraries have been used to map epitopes for antibody binding, to discern ribonucleotide sequences with specific binding or catalytic activity, and to provide initial leads in receptor-based assays. Advantages of these oligomeric molecules are an almost limitless diversity as a result of their modular structure, the ease with which they can be synthesized and sequenced, and their inherent biological relevance. On the other hand, the metabolic instability of peptides and nucleotides and their poor absorption characteristics mean that any lead sequence will require extensive modification before in vivo activity can be expected.Many of these problems could be avoided if an alternative, modular system was devised, with a basis set of "unnatural" monomers and a method for their controlled oligomerization. A host of chemically and pharmaceutically interesting subunits or modules would generate a diverse and novel set of heteropolymers. Once an interesting compound has been identified from a library of such nonpeptide polymers, it can serve as a lead for drug discovery, further along the road to a metabolically stable drug. Optimized analogs of a lead compound could then be developed rapidly due to the modular synthetic nature of th...

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 N atural antimicrobial peptides (AMPs) defend a wide array of organisms against bacterial pathogens and show potential as supplements for or replacements of conventional antibiotics, because few bacteria have evolved resistance to them (1-3). Many AMPs kill bacteria by permeabilization of the cytoplasmic membrane, causing depolarization, leakage, and death (4), whereas others target additional anionic bacterial constituents (e.g., DNA, RNA, or cell wall components) (2, 5). Amphipathic secondary structures in which residues are segregated into hydrophobic and cationic regions ( Fig. 1 A and B) are the hallmark of most AMPs (6). Regardless of their final target of killing, AMPs must interact with the bacterial cytoplasmic membrane, and their amphipathicity is integral to such interactions (1, 2, 7). Additionally, their cationic nature imparts AMPs with some measure of selectivity, because mammalian cell membranes are largely zwitterionic. The precise nature of AMP-membrane interactions remains controversial and actively debated; a variety of mechanisms have been proposed, including the carpet (4), barrel-stave pore (4), toroidal pore (8), and aggregate (9) models. Nevertheless, a considerable number of structure-activity investigations have elucidated how the physicochemical properties of these molecules relate to their biological activities (4,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).Although AMPs have been actively studied for decades (23-25), they have yet to see widespread clinical use (1). This is due in part to the vulnerability of many peptide therapeutics to rapid in vivo degradation, which dramatically reduces their bioavailability. Nonnatural mimics of AMPs...

The design and synthesis of protein-like polymers is a fundamental challenge in materials science. A biomimetic approach is to explore the impact of monomer sequence on non-natural polymer structure and function. We present the aqueous self-assembly of two peptoid polymers into extremely thin two-dimensional (2D) crystalline sheets directed by periodic amphiphilicity, electrostatic recognition and aromatic interactions. Peptoids are sequence-specific, oligo-N-substituted glycine polymers designed to mimic the structure and functionality of proteins. Mixing a 1:1 ratio of two oppositely charged peptoid 36mers of a specific sequence in aqueous solution results in the formation of giant, free-floating sheets with only 2.7 nm thickness. Direct visualization of aligned individual peptoid chains in the sheet structure was achieved using aberration-corrected transmission electron microscopy. Specific binding of a protein to ligand-functionalized sheets was also demonstrated. The synthetic flexibility and biocompatibility of peptoids provide a flexible and robust platform for integrating functionality into defined 2D nanostructures.

Here we demonstrate Au nanoparticle self-similar chain structure organized by triangle DNA origami with well-controlled orientation and <10 nm spacing. We show for the first time that a large DNA complex (origami) and multiple AuNP conjugates can be well-assembled and purified with reliable yields. The assembled structure could be used to generate high local-field enhancement. The same method can be used to precisely localize multiple components on a DNA template for potential applications in nanophotonic, nanomagnetic, and nanoelectronic devices.