Synthesis of Side-Chain Modified Polypeptides

Deming, Timothy J.

doi:10.1021/acs.chemrev.5b00292

Cited by 366 publications

(360 citation statements)

References 146 publications

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“…42 Recently, a number of oligoethylene glycol functionalized R-C polypeptides have been prepared, which either form poorly soluble β-sheets in water, or form β-sheets at elevated temperature in water with longer ethylene glycol repeats (i.e. > 3-4).…”

Section: R-cmentioning

confidence: 99%

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

Deming

2017

Bioconjugate Chem.

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Recent developments in the modification of methionine and other thioether containing residues in peptides, polypeptides and proteins are reviewed. Properties and potential applications of the resulting functionalized products are also discussed. While much of this work is focused on natural Met residues, modifications at other side-chain residues have also emerged as new thioether containing amino acids have been incorporated into peptidic materials. Functional modification of thioether containing amino acids has many advantages, and is complimentary methodology to the widely utilized methods for modification at cysteine residues.

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Section: R-cmentioning

confidence: 99%

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

Deming

2017

Bioconjugate Chem.

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“…Polypeptides are widely explored for drug delivery and regenerative medicine. [20][21][22][23][24][25][26][27] Vitamin E is a well-known natural antioxidant and its derivatives have been reported to enhance therapeutic delivery. 28,29 It should be noted that the hydrophobic vitamin E head portion and hydrophilic oligopeptide tail are bulky and have large surface areas, which is an essential characteristic of a good surfactant.…”

Section: Introductionmentioning

confidence: 99%

Vitamin E-Oligo(methyl diglycol l-glutamate) as a Biocompatible and Functional Surfactant for Facile Preparation of Active Tumor-Targeting PLGA Nanoparticles

Zhang

Deng

et al. 2016

Biomacromolecules

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Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles have attracted an enormous interest for controlled drug delivery. Their clinical applications are, however, partly hindered by lack of biocompatible, biodegradable and functional surfactants. Here, we designed and developed a novel biocompatible surfactant based on amphiphilic vitamin E-oligo(methyl diglycol l-glutamate) (VEOEG) for facile fabrication of robust and tumor-targeting PLGA-based nanomedicines. VEOEG was prepared with controlled Mn of 1.7-2.6 kg/mol and low molecular weight distribution (Đ = 1.04-1.16) via polymerization of methyl diglycol l-glutamate N-carboxyanhydride using vitamin E-ethylenediamine derivative (VE-NH2) as an initiator. VEOEG had a hydrophile-lipophile balance data of 13.8-16.1 and critical micellar concentration of 189.3-203.8 mg/L depending on lengths of oligopeptide. Using VEOEG as a surfactant, PLGA nanoparticles could be obtained via nanoprecipitation method with a small and uniform hydrodynamic size of 135 nm and positive surface charge of +26.6 mV, in accordance with presence of amino groups at the surface. The resulting PLGA nanoparticles could be readily coated with hyaluronic acid (HA) to form highly stable, small-sized (143 nm), monodisperse, and negatively charged nanoparticles (HA-PLGA NPs). Notably, paclitaxel-loaded HA-PLGA NPs (PTX-HA-PLGA NPs) exhibited better antitumor effects in CD44-positive MCF-7 breast tumor cells than Taxol (a clinical paclitaxel formulation). The in vivo pharmacokinetics assay in nude mice displayed that PTX-HA-PLGA NPs possessed a long plasma half-life of 3.14 h. The in vivo biodistribution studies revealed that PTX-HA-PLGA NPs had a high tumor PTX level of 8.4% ID/g, about 6 times better than that of Taxol. Interestingly, therapeutic studies showed that PTX-HA-PLGA NPs caused significantly more effective tumor growth inhibition, better survival rate and lower adverse effect than Taxol. VEOEG has emerged as a versatile and functional surfactant for the fabrication of advanced anticancer nanomedicines.

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“…While designing the M6P-GP synthesis, routes involving polymerization of M6P containing α-NCA and installation of M6P moiety postpolymerization were considered. 30 Although glycopolypeptides have been synthesized by post polymerization methods, 31−34 they do not ensure 100% glycosylation density on the side chains. To enable a formation of 100% glycosylated M6P-GPs, we undertook an approach that combined the preparation and polymerization of a M6P-functionalized NCA monomer.…”

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confidence: 99%

Controlled Synthesis of End-Functionalized Mannose-6-phosphate Glycopolypeptides for Lysosome Targeting

et al. 2016

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The ubiquitous expression of the mannose-6-phosphate receptor on the majority of human cells makes it a valid target in the quest to deliver therapeutics selectively to the lysosome. In this work end-functionalized polyvalent mannose-6-phosphate glycopolypeptides (M6P-GPs) with high molecular weights (up to 22 kDa) have been synthesized via NCA polymerization. These synthetic M6P-GPs were found to display minimal toxicity to cells in vitro and show exceptional selectivity for trafficking into lysosomes in various cell lines. Comparison of the cellular uptake behavior of M6P-GP and the corresponding mannose-GP polymer reveals that incorporation of the phosphate moiety at the 6-position of mannose completely alters its trafficking behavior and becomes exclusively lysosome specific. We also demonstrate that trafficking of M6P-GPs in mammalian cells is likely associated with the CI-MPR receptor pathway. I n mammalian cells, mannose-6-phosphate receptors play a critical role in the sorting of lysosomal enzymes from secretory proteins and their subsequent delivery into lysosomes. 1 These receptors, which include the ∼300 kDa insulin-like growth factor-II (IGF-II)/cation-independent (CI) multifunctional transmembrane glycoprotein mannose-6-phosphate (M6P) receptor (CI-MPR), bind lysosomal enzymes containing phosphomannosyl residues in the trans-golgi network (TGN) and transport them to endosomes where the low pH leads to the dissociation of the ligand−receptor complex. 2 The receptors then return to the TGN to repeat another round of this process. As a result, the receptor CI-MPR is largely localized in the intracellular compartments and shuttles between TGN and endosomes with ∼10% of the receptor being present on the cell surface. 3 Additionally, the CI-MPR receptor is overexpressed in the early stage of several cancers, particularly in breast and prostate cancer, and hence can serve as an early marker for these cancers. 4,5 The ability of CI-MPR to deliver cargo specifically to the lysosome can thus be selectively targeted using M6P-labeled carriers to dispatch cytotoxic drugs inside lysosomes for destroying cancer cells. 6−8 In addition, CI-MPR can be targeted to deliver M6P-labeled enzymes into lysosomes for enzyme replacement therapies (ERTs) in non-neural lysosomal storage disorders (LSDs). 9,10 LSDs are a group of more than 40 metabolic disorders that result from the deficient activity of specific lysosomal enzymes inside the lysosomes leading to progressive accumulation of its substrate inside the cell. Nowadays several M6P-modified enzymes are used clinically for the treatment of LSD. However, the low levels of M6P modification dramatically reduce its binding efficiency to the receptor, and hence relatively high doses of these enzymes need to be administered to achieve significant therapeutic efficacy. 11 Modification of lysosomal enzymes with higher amounts of M6P residues for enhanced targeted delivery remains a critical challenge. 12 Previous studies demonstrate that CI-MPR exists as a dimer in the membrane ...

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Synthesis of Side-Chain Modified Polypeptides

Cited by 366 publications

References 146 publications

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

Vitamin E-Oligo(methyl diglycol l-glutamate) as a Biocompatible and Functional Surfactant for Facile Preparation of Active Tumor-Targeting PLGA Nanoparticles

Controlled Synthesis of End-Functionalized Mannose-6-phosphate Glycopolypeptides for Lysosome Targeting

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