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John R Edison, Ryan K Spencer, Glenn L Butterfoss, Benjamin C Hudson, Allon I Hochbaum, Anant K Paravastu, Ronald N Zuckermann, Stephen Whitelam
The conformations adopted by the molecular constituents of a supramolecular assembly influence its large-scale order. At the same time, the interactions made in assemblies by molecules can influence their conformations. Here we study this interplay in extended flat nanosheets made from nonnatural sequence-specific peptoid polymers. Nanosheets exist because individual polymers can be linear and untwisted, by virtue of polymer backbone elements adopting alternating rotational states whose twists oppose and cancel...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Q Nhu N Nguyen, Joshua Schwochert, Dean J Tantillo, R Scott Lokey
Solving conformations of cyclic peptides can provide insight into structure-activity and structure-property relationships, which can help in the design of compounds with improved bioactivity and/or ADME characteristics. The most common approaches for determining the structures of cyclic peptides are based on NMR-derived distance restraints obtained from NOESY or ROESY cross-peak intensities, and 3J-based dihedral restraints using the Karplus relationship. Unfortunately, these observables are often too weak, sparse, or degenerate to provide unequivocal, high-confidence solution structures, prompting us to investigate an alternative approach that relies only on 1H and 13C chemical shifts as experimental observables...
May 10, 2018: Physical Chemistry Chemical Physics: PCCP
R Kaminker, I Kaminker, W R Gutekunst, Y Luo, S Lee, J Niu, S Han, C J Hawker
We demonstrate that changing the backbone between peptides, peptoids and the underexplored dual N/Cα-substituted peptoids analogues allows for control over the preferred conformation of the intrinsically disordered biomimetic oligomers. The conformation tunability is directly probed using electron paramagnetic resonance (EPR), and is shown to manifest itself in differences in the nanoparticle-oligomer hybridization propensity.
May 4, 2018: Chemical Communications: Chem Comm
Ann M Czyzewski, Lynda M McCaig, Michelle T Dohm, Lauren A Broering, Li-Juan Yao, Nathan J Brown, Maruti K Didwania, Jennifer S Lin, Jim F Lewis, Ruud Veldhuizen, Annelise E Barron
Acute lung injury (ALI) leads to progressive loss of breathing capacity and hypoxemia, as well as pulmonary surfactant dysfunction. ALI's pathogenesis and management are complex, and it is a significant cause of morbidity and mortality worldwide. Exogenous surfactant therapy, even for research purposes, is impractical for adults because of the high cost of current surfactant preparations. Prior in vitro work has shown that poly-N-substituted glycines (peptoids), in a biomimetic lipid mixture, emulate key biophysical activities of lung surfactant proteins B and C at the air-water interface...
May 1, 2018: Scientific Reports
Aanchal Mohan, Allyson H M Koh, Gregory Gate, Anna L Calkins, Kyra N McComas, Amelia A Fuller
Peptidomimetics that can coordinate transition metals have a variety of potential applications as catalysts, sensors, or materials. A new modular peptidomimetic scaffold, the “azole peptoid”, is introduced here. We report methods for the solid-phase synthesis of eleven examples of trimeric N -substituted oligoamides that include oxazole- or thiazole-functionalized backbones. The products prepared comprise a diversity of functionality, including a metal-coordinating terpyridine group. The modular synthetic approach enables ready preparation of analogs for specific applications...
April 28, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Totan Ghosh, Natalia Fridman, Monica Kosa, Galia Maayan
Metal-ligand coordination is a key interaction in the self-assembly of biopolymers. Although binding of metal ions to synthetic proteins and peptides is known to yield high-order structures, self-assembly of peptidomimetic molecules upon metal binding is still challenging. Herein we explore the self-assembly of three peptoid trimers 3, 3A and 3B, bearing a bipyridine ligand at their C-terminus, a benzyl group at their N-terminus and a polar group (N-ethyl-R) in the middle position (R = OH, OCH3 and NH2, respectively) by Cu2+ coordination...
April 18, 2018: Angewandte Chemie
Benjamin C Hudson, Alessia Battigelli, Michael D Connolly, John Edison, Ryan K Spencer, Stephen Whitelam, Ronald N Zuckermann, Anant K Paravastu
Peptoid nanosheets are supramolecular protein-mimetic materials that form from amphiphilic polypeptoids with aromatic and ionic sidechains. Nanosheets have been studied at the nanometer scale, but molecular structure has been difficult to probe. We report the use of 13 C-13 C dipolar recoupling solid-state NMR measurements to reveal the configuration of backbone amide bonds selected by 13 C isotopic labeling of adjacent α-carbons. Measurements on the same molecules in the amorphous state and in nanosheets revealed that amide bonds in the center of the amino block of peptoid (NaeNpe)7 -(NceNpe)7 (B28) favor the trans configuration in the amorphous state and the cis configuration in the nanosheet...
April 16, 2018: Journal of Physical Chemistry Letters
Konstantin Andreev, Michael W Martynowycz, Mia L Huang, Ivan Kuzmenko, Wei Bu, Kent Kirshenbaum, David Gidalevitz
Hydrophobic interactions govern specificity for natural antimicrobial peptides. No such relationship has been established for synthetic peptoids that mimic antimicrobial peptides. Peptoid macrocycles synthesized with five different aromatic groups are investigated by minimum inhibitory and hemolytic concentration assays, epifluorescence microscopy, atomic force microscopy, and X-ray reflectivity. Peptoid hydrophobicity is determined using high performance liquid chromatography. Disruption of bacterial but not eukaryotic lipid membranes is demonstrated on the solid supported lipid bilayers and Langmuir monolayers...
April 2, 2018: Biochimica et Biophysica Acta
Sylvia Natalie Kłodzińska, Natalia Molchanova, Henrik Franzyk, Paul Robert Hansen, Peter Damborg, Hanne Mørck Nielsen
Infections caused by Pseudomonas aeruginosa are associated with high morbidity and mortality, especially in immunocompromised patients. These bacteria frequently grow within a biofilm matrix, rendering therapy with conventional antibiotics inefficient; a fact that emphasizes the need for new treatment strategies. Antimicrobial peptidomimetics constitute potential alternatives to traditional antimicrobial agents, however, their application remains limited due to the lack of efficient delivery to their target site in vivo and the risk of high systemic toxicity...
March 29, 2018: European Journal of Pharmaceutics and Biopharmaceutics
Ho Yeon Nam, Jong-Ah Hong, Jieun Choi, Seungheon Shin, Steve K Cho, Jiwon Seo, Jiyoun Lee
Mitochondria-specific delivery methods offer a valuable tool for studying mitochondria-related diseases and provide breakthroughs in therapeutic development. Although several small-molecule and peptide-based transporters have been developed, peptoids, proteolysis-resistant peptidomimetics, are a promising alternative to current approaches. We designed a series of amphipathic peptoids and evaluated their cellular uptake and mitochondrial localization. Two peptoids with cyclohexyl residues demonstrated highly efficient cell penetration and mitochondrial localization without significant adverse effects on the cells and mitochondria...
March 26, 2018: Bioconjugate Chemistry
Keitou Shu, Thomas Kodadek
One-bead-one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are comprised of oligoamides, particularly peptides, peptoids and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Towards this end, we report here the efficient proline-catalyzed asymmetric aldol reaction between immobilized aldehydes and soluble ketones. These reaction conditions do not compromise the amplification of DNA by the polymerase chain reaction...
March 26, 2018: ACS Combinatorial Science
Jianhua Ren, Yadwinder S Mann, Yuntao Zhang, Michael D Browne
Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have been thought of as a type of molecular information storage. Mass spectrometry analysis has been considered the method of choice for sequencing peptoids. Peptoids can be synthesized via solid phase chemistry using a repeating two-step reaction cycle. Here we present a method to manually synthesize oligo-peptoids and to analyze the sequence of the peptoids using tandem mass spectrometry (MS/MS) techniques...
February 21, 2018: Journal of Visualized Experiments: JoVE
Ines Greco, Bernard D Hummel, Jaspreet Vasir, Jeffrey L Watts, Jason Koch, Johannes E Hansen, Hanne Mørck Nielsen, Peter Damborg, Paul R Hansen
Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N -alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, B1 and D2 , which are effective against the canine skin pathogen Staphylococcus pseudintermedius , the main cause of antibiotic use in companion animals. We report on their potential to treat infections topically by characterizing their release from formulation and in vitro ADME properties...
March 10, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Satya Prakash Shukla, D Gomika Udugamasooriya
We recently identified a peptide-peptoid hybrid, PPS1, which specifically recognized lipid-phosphatidylserine (PS). PPS1 consists of distinct positively charged and hydrophobic residue-containing regions. PPS1 monomer was inactive, but the dimeric form, PPS1D1, displayed strong cytotoxicity for lung cancer cells compared to normal cells in vitro, and reduced the tumor growth in vivo. The minimum pharmacophore of PPS1D1 showed that the first (methionine) and fourth (N-lysine) residues were not important for PPS1D1 cytotoxic activity...
December 1, 2017: MedChemComm
Alessia Battigelli, Jae Hong Kim, Dilani C Dehigaspitiya, Caroline Proulx, Ellen J Robertson, Daniel J Murray, Behzad Rad, Kent Kirshenbaum, Ronald N Zuckermann
Glycoproteins adhered on the cellular membrane play a pivotal role in a wide range of cellular functions. Their importance is particularly relevant in the recognition process between infectious pathogens (such as viruses, bacteria, toxins) and their host cells. Multivalent interactions at the pathogen-cell interfaces govern binding events and can result in a strong and specific interaction. Here we report an approach to mimic the cell surface presentation of carbohydrate ligands by the multivalent display of sugars on the surface of peptoid nanosheets...
March 27, 2018: ACS Nano
Garrett L Sternhagen, Sudipta Gupta, Yueheng Zhang, Vijay John, Gerald J Schneider, Donghui Zhang
A series of amphiphilic ionic peptoid block copolymers where the total number (1 or 3) and position of ionic monomers along the polymer chain are precisely controlled have been synthesized by the submonomer method. Upon dissolution in water at pH = 9, the amphiphilic peptoids self-assemble into small spherical micelles having hydrodynamic radius in ∼5-10 nm range and critical micellar concentration (CMC) in the 0.034-0.094 mg/mL range. Small-angle neutron scattering (SANS) analysis of the micellar solutions revealed unprecedented dependence of the micellar structure on the number and position of ionic monomers along the chain...
March 21, 2018: Journal of the American Chemical Society
Min-Kyung Shin, Yu-Jung Hyun, Ji Hoon Lee, Hyun-Suk Lim
Cyclic peptoids are emerging as an attractive class of peptidomimetics. Compared to their linear counterparts, cyclic peptoids should have increased conformational rigidity and preorganized structures, enabling them to bind more tightly to target proteins without major entropy penalty. Because cyclic peptoids lack the amide protons in their backbones like linear peptoids, it is perceived that cyclic peptoids are seemingly cell permeable as much as linear peptoids. However, no systematic investigation for cell permeability of cyclic peptoids has been reported yet...
April 9, 2018: ACS Combinatorial Science
Yung-Ching Chien, Jinhui Tao, Kuniko Saeki, Alexander F Chin, Jolene L Lau, Chun-Long Chen, Ronald N Zuckermann, Sally J Marshall, Grayson W Marshall, James J De Yoreo
In calcified tissues such as bones and teeth, mineralization is regulated by an extracellular matrix, which includes non-collagenous proteins (NCP). This natural process has been adapted or mimicked to restore tissues following physical damage or demineralization by using polyanionic acids in place of NCPs, but the remineralized tissues fail to fully recover their mechanical properties. Here we show that pre-treatment with certain amphiphilic peptoids, a class of peptide-like polymers consisting of N-substituted glycines that have defined monomer sequences, enhances ordering and mineralization of collagen and induces functional remineralization of dentin lesions in vitro ...
December 11, 2017: ACS Biomaterials Science & Engineering
Chad Townsend, Akihiro Furukawa, Joshua Schwochert, Cameron R Pye, Quinn Edmondson, R Scott Lokey
Cyclic peptides are of great interest as therapeutic compounds due to their potential for specificity and intracellular activity, but specific compounds can be difficult to identify from large libraries without resorting to molecular encoding techniques. Large libraries of cyclic peptides are often DNA-encoded or linearized before sequencing, but both of those deconvolution strategies constrain the chemistry, assays, and quantification methods which can be used. We developed an automated sequencing program, CycLS, to identify cyclic peptides contained within large synthetic libraries...
March 15, 2018: Bioorganic & Medicinal Chemistry
Arushi Prakash, Marcel D Baer, Christopher J Mundy, Jim Pfaendtner
Peptoids are peptide-mimetic biopolymers that are easy to synthesize and adaptable for use in drugs, chemical scaffolds, and coatings. However, there is insufficient information about their structural preferences and interactions with the environment in various applications. We conducted a study to understand the fundamental differences between peptides and peptoids using molecular dynamics simulations with semiempirical (PM6) and empirical (AMBER) potentials, in conjunction with metadynamics enhanced sampling...
March 12, 2018: Biomacromolecules
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