139115-90-5Relevant articles and documents
Stapling of two PEGylated side chains increases the conformational stability of the WW domain via an entropic effect
Xiao, Qiang,Bécar, Natalie A.,Brown, Nathaniel P.,Smith, Mason S.,Stern, Kimberlee L.,Draper, Steven R.E.,Thompson, Katherine P.,Price, Joshua L.
, p. 8933 - 8939 (2018)
Hydrocarbon stapling and PEGylation are distinct strategies for enhancing the conformational stability and/or pharmacokinetic properties of peptide and protein drugs. Here we combine these approaches by incorporating asparagine-linked O-allyl PEG oligomers at two positions within the β-sheet protein WW, followed by stapling of the PEGs via olefin metathesis. The impact of stapling two sites that are close in primary sequence is small relative to the impact of PEGylation alone and depends strongly on PEG length. In contrast, stapling of two PEGs that are far apart in primary sequence but close in tertiary structure provides substantially more stabilization, derived mostly from an entropic effect. Comparison of PEGylation + stapling vs. alkylation + stapling at the same positions in WW reveals that both approaches provide similar overall levels of conformational stability.
Helix versus coil polypeptide macromers: Gel networks with decoupled stiffness and permeability
Oelker, Abigail M.,Hammond, Paula T.,Morey, Shannon M.,Griffith, Linda G.
, p. 10887 - 10895,9 (2012)
As a platform for investigating the individual effects of substrate stiffness, permeability, and ligand density on cellular behavior, we developed a set of hydrogels with stiffness tuned by polymer backbone rigidity, independent of cross-link density and concentration. Previous studies report that poly(propargyl-l-glutamate) (PPLG), synthesized by ring-opening polymerization of the N-carboxy anhydride of γ-propargyl-l-glutamate (γplglu), adopts a rigid a-helix conformation: we hypothesized that a random copolymer (PPDLG) with equal amounts of γplglu and γ-propargyl-d-glutamate (γpdglu) monomers would exhibit a more flexible random coil conformation. The resulting macromers exhibited narrow molecular weight distributions (PDI = 1.15) and were grafted with ethylene glycol groups using a highly efficient "click" azide/alkyne cycloaddition reaction with average grafting efficiency of 97% for PPLG and 85% for PPDLG. The polypeptide secondary structure, characterized via circular dichroism spectroscopy, FTIR spectroscopy, and dynamic light scattering, is indeed dependent upon monomer chirality: PPLG exhibits an α-helix conformation while PPDLG adopts a random coil conformation. Hydrogel networks produced by cross-linking either helical or random coil polypeptides with poly(ethylene glycol) (PEG) were analyzed for amount of swelling, gelation efficiency, and permeability to a model protein. In addition, the elastic modulus of helical and coil polypeptide gels was determined by AFM indentation in fluid. Importantly, we found that helical and coil polypeptide gels exhibited similar swelling and permeability but different stiffnesses, which correspond to predictions from the theory of semi-flexible chains. This journal is
Redefining Protein Interfaces within Protein Single Crystals with DNA
Han, Zhenyu,Mirkin, Chad A.,Partridge, Benjamin E.,Winegar, Peter H.
, p. 8925 - 8934 (2021)
Proteins are exquisite nanoscale building blocks: molecularly pure, chemically addressable, and inherently selective for their evolved function. The organization of proteins into single crystals with high positional, orientational, and translational order results in materials where the location of every atom can be known. However, controlling the organization of proteins is challenging due to the myriad interactions that define protein interfaces within native single crystals. Recently, we discovered that introducing a single DNA-DNA interaction between protein surfaces leads to changes in the packing of proteins within single crystals and the protein-protein interactions (PPIs) that arise. However, modifying specific PPIs to effect deliberate changes to protein packing is an unmet challenge. In this work, we hypothesized that disrupting and replacing a highly conserved PPI with a DNA-DNA interaction would enable protein packing to be modulated by exploiting the programmability of the introduced oligonucleotides. Using concanavalin A (ConA) as a model protein, we circumvent potentially deleterious mutagenesis and exploit the selective binding of ConA toward mannose to noncovalently attach DNA to the protein surface. We show that DNA association eliminates the major PPI responsible for crystallization of native ConA, thereby allowing subtle changes to DNA design (length, complementarity, and attachment position) to program distinct changes to ConA packing, including the realization of three novel crystal structures and the deliberate expansion of ConA packing along a single crystallographic axis. These findings significantly enhance our understanding of how DNA can supersede native PPIs to program protein packing within ordered materials.
Effect of side-wall functionalisation of multi-walled carbon nanotubes on the thermo-mechanical properties of epoxy composites
Konnola, Raneesh,Joseph, Kuruvilla
, p. 23887 - 23899 (2016)
In this work, a novel functionalisation was carried out by grafting carboxyl-terminated poly(acrylonitrile-co-butadiene) on the side-walls of multi-walled carbon nanotubes to prepare MWCNT-g-CTBN. The functionalized nanotubes were characterized by XPS, Raman spectroscopy, and TGA and the surface morphology was analyzed by transmission electron microscopy. The dispersion behavior of the MWCNT/epoxy nanosuspension was carefully analyzed by transmission optical microscopy (TOM) and rheology. The MWCNT-g-CTBN was added to the diglycidyl ether of bisphenol A-type epoxy to prepare MWCNT-g-CTBN/epoxy composites. Incorporation of CTBN-grafted MWCNTs in epoxy matrix imparted tremendous improvement in mechanical strength as well as fracture toughness when compared with pristine MWCNT/epoxy composites. The mechanism for this improvement in mechanical properties is attributed to the increase in interfacial strength between nanotubes and the epoxy matrix through chemical bonding. The toughening mechanism that leads to the enhancement in the fracture toughness of the nanocomposites was assessed with the help of Field Emission Scanning Electron Microscopy (FESEM). Dynamic mechanical analysis of the MWCNT-g-CTBN/epoxy composite revealed an increase in the Tg of the epoxy phase as well as an increase in modulus due to the enhancement in stiffness of the material.
A convergent synthesis of heterocyclic dendrimers using the 1,3-dipolar cycloaddition reaction of organic azides and acetylenedicarboxylate esters
Van Wuytswinkel, Grete,Verheyde, Bert,Compernolle, Frans,Toppet, Suzanne,Dehaen, Wim
, p. 1337 - 1340 (2000)
The convergent synthesis of heterocyclic dendrimers using 1,3-dipolar cycloaddition reaction of organic azides and acetylenedicarboxylate esters was discussed. It was found that the second generation dibromofumarate was prepared from monomer and the first
Design, synthesis, and biological evaluation of proteolysis targeting chimeras (PRoTACS) for the dual degradation of IGF-1R and SrC
Lee, Jeeyeon,Lee, Na Keum,Manda, Sudhakar,Oh, Dong-Chan
, (2020)
A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a–b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1–5 μM) in various cellular assays.
Selectively Targeting and Differentiating Vancomycin-Resistant Staphylococcus aureus via Dual Synthetic Fluorescent Probes
Wang, Tsung-Shing Andrew,Chen, Pin-Lung,Chen, Yi-Chen Sarah,Hung, Hsuan-Min,Huang, Jhih-Yi
, p. 2584 - 2590 (2021)
Many Staphylococcus bacteria are pathogenic and harmful to humans. Noticeably, some Staphylococcus, including vancomycin-resistant S. aureus (VRSA), have become notoriously resistant to antibiotics and have spread rapidly, becoming threats to public health. Here, we designed a dual fluorescent probe scheme combining siderophores and antibiotics as the guiding units to selectively target VRSA and vancomycin-sensitive S. aureus (VSSA) in complex bacterial samples. Siderophore-mediated iron uptake is the key pathway by which S. aureus acquires iron in limited environments. Therefore, the siderophore-derivative probe could differentiate between S. aureus and other bacteria. Moreover, by fine-tuning the vancomycin-derivative probes, we could selectively target only VSSA, further differentiating VRSA and VSSA. Finally, by combining the siderophore-derivative probe and the vancomycin-derivative probe, we successfully targeted and differentiated between VRSA and VSSA in complicated bacterial mixtures.
Glyco-functionalized dinuclear rhenium(i) complexes for cell imaging
Palmioli, Alessandro,Aliprandi, Alessandro,Septiadi, Dedy,Mauro, Matteo,Bernardi, Anna,De Cola, Luisa,Panigati, Monica
, p. 1686 - 1699 (2017)
The design, synthesis and photophysical characterization of four new luminescent glycosylated luminophores based on dinuclear rhenium complexes, namely Glyco-Re, are described. The derivatives have the general formula [Re2(μ-Cl)2(CO)
Hypoxia-Responsive19F MRI Probes with Improved Redox Properties and Biocompatibility
Xie, Da,Kim, Seyong,Kohli, Vikraant,Banerjee, Arnab,Yu, Meng,Enriquez, José S.,Luci, Jeffrey J.,Que, Emily L.
, p. 6429 - 6437 (2017)
19F magnetic resonance imaging (MRI), an emerging modality in biomedical imaging, has shown promise for in vitro and in vivo preclinical studies. Here we present a series of fluorinated Cu(II)ATSM derivatives for potential use as19F magnetic resonance agents for sensing cellular hypoxia. The synthesized complexes feature a hypoxia-targeting Cu2+ coordination core, nine equivalent fluorine atoms connected via a variable-length poly(ethylene glycol) linker. Introduction of the fluorine moiety maintains the planar coordination geometry of the Cu2+ center, while the linker length modulates the Cu2+/+ reduction potential,19F NMR relaxation properties, and lipophilicity. In particular, the19F NMR relaxation properties were quantitatively evaluated by the Solomon-Bloembergen model, revealing a regular pattern of relaxation enhancement tuned by the distance between Cu2+ and F atoms. Finally, the potential utility of these complexes for sensing reductive environments was demonstrated using both19F MR phantom imaging and19F NMR, including experiments in intact live cells.
Spatially well-defined carbohydrate nanoplatforms: Synthesis, characterization and lectin interaction study
Timmer,Flos, M. Abellán,J?rgensen, L. M?nster,Proverbio,Altun,Ramstr?m,Aastrup,Vincent
, p. 12326 - 12329 (2016)
Two novel dodecasubstituted carbohydrate nanoplatforms based on molecular Borromean rings and dodecaamine cages have been prepared for use in evaluating the importance of the spatial distribution of carbohydrates in their interaction with lectins. The binding affinities of the glyconanoplatforms were characterized using quartz crystal microbalance technology and compared with a monovalent reference and dodecaglycosylated fullerenes.
