Development of Homomultimers and Heteromultimers of Lung Cancer-Specific Peptoids
ABSTRACT Multimeric interactions that occur in biology provide impetus for chemists to explore new types of synthetic multivalent ligands that alter cellular functions by mechanisms inaccessible to natural substances. While many different molecules such as peptides, antibody fragments, carbohydrates and organic moieties have been used in developing multimeric ligands, it is worth exploring other important molecular types that have hardly been tested in developing multimeric compounds. Peptoids are one such class of compounds with highly facile synthesis as well as much better biologically amenable qualities. Recently, we identified two HCC4017 lung cancer cell targeting peptoids. Here we explore the possibility of synthesizing multimers of these compounds completely through a solid phase synthesis approach. We have synthesized mini-libraries of homodimers, homotrimers and most importantly, heterodimers of our lung cancer specific compounds. The idea is to develop series of compounds that only differs by the linker portion, which is readily adjustable within the library. The purpose of this is to find the optimal distance between each monomeric unit of the multimer that allows them to perfectly interact with their individual biological targets displayed on the cell surface. Future screens of these minilibraries will identify the multimers with improved binding affinities.
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- "However, the p-methoxybenzylamine containing peptoids were synthesized with rather low yields (2.1–2.7%). This side chain is quite acid sensitive and leads therefore to degradation [45,46,47]. In general, the concept of MiniKan-based peptoid libraries proved to be compatible with the widely used submomomer approach and should thus be applicable to the synthesis of large and diverse libraries. "
ABSTRACT: Cell penetrating peptoids (CPPos) are potent mimics of the corresponding cell penetrating peptides (CPPs). The synthesis of diverse oligomeric libraries that display a variety of backbone scaffolds and side-chain appendages are a very promising source of novel CPPos, which can be used to either target different cellular organelles or even different tissues and organs. In this study we established the submonomer-based solid phase synthesis of a "proof of principle" peptoid library in IRORI MiniKans to expand the amount for phenotypic high throughput screens of CPPos. The library consisting of tetrameric peptoids [oligo(N-alkylglycines)] was established on Rink amide resin in a split and mix approach with hydrophilic and hydrophobic peptoid side chains. All CPPos of the presented library were labeled with rhodamine B to allow for the monitoring of cellular uptake by fluorescent confocal microscopy. Eventually, all the purified peptoids were subjected to live cell imaging to screen for CPPos with organelle specificity. While highly charged CPPos enter the cells by endocytosis with subsequent endosomal release, critical levels of lipophilicity allow other CPPos to specifically localize to mitochondria once a certain lipophilicity threshold is reached.Pharmaceuticals 12/2012; 5(12):1265-1281. DOI:10.3390/ph5121265
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ABSTRACT: Bioinspired polymeric materials are attracting increasing attention due to significant advantages over their natural counterparts: the ability to precisely tune their structures over a broad range of chemical and physical properties, increased stability, and improved processability. Polypeptoids, a promising class of bioinspired polymer based on a N-substituted glycine backbone, have a number of unique properties that bridge the material gap between proteins and bulk polymers. Peptoids combine the sequence specificity of biopolymers with the simpler intra/intermolecular interactions and robustness of traditional synthetic polymers. They are highly designable because hundreds of chemically diverse side chains can be introduced from simple building blocks. Peptoid polymers can be prepared by two distinct synthetic techniques offering access to two material subclasses: (1) automated solid-phase synthesis which enables precision sequence control and near absolute monodispersity up to chain lengths of ∼50 monomers, and (2) a classical polymerization approach which allows access to higher molecular weights and larger-scale yields, but with less control over length and sequence. This combination of facile synthetic approaches makes polypeptoids a highly tunable, rapid polymer prototyping platform to investigate new materials that are intermediate between proteins and bulk polymers, in both their structure and their properties. In this paper, we review the methods to synthesize peptoid polymers and their applications in biomedicine and nanoscience, as both sequence-specific materials and as bulk polymers.ACS Nano 05/2013; 7(6). DOI:10.1021/nn4015714 · 12.88 Impact Factor
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ABSTRACT: The glycocalyx of the cell is composed of highly hydrated saccharidic groups conjugated to protein and lipid cores. Although components of the glycocalyx are important in cell-cell interactions and other specific biological recognition events, a fundamental role of the glycocalyx is the inhibition of nonspecific interactions at the cell surface. Inspired by glycoproteins present in the glycocalyx, we describe a new class of synthetic antifouling polymer composed of saccharide containing N-substituted polypeptide (glycopeptoid). Grafting of glycopeptoids to a solid surface resulted in a biomimetic shielding layer that dramatically reduced nonspecific protein, fibroblast and bacterial cell attachment. All-atom molecular dynamics simulation of grafted glycopeptoids revealed an aqueous interface enriched in highly hydrated saccharide residues. In comparison to saccharide-free peptoids, the interfacial saccharide residues of glycopeptoids formed a higher number of hydrogen bonds with water molecules. Moreover, these hydrogen bonds displayed a longer persistence time, which we believe contributed to fouling resistance by impeding interactions with biomolecules. Our findings suggest that the fouling resistance of glycopeptoids can be explained by the presence of both a 'water barrier' effect associated with the hydrated saccharide residues, as well as steric hindrance from the polymer backbone.Journal of the American Chemical Society 08/2013; 135(35). DOI:10.1021/ja404681x · 12.11 Impact Factor