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Carbohydrate Polymers Nov 2023Heparosan is an acidic polysaccharide expressed as a capsule polymer by pathogenic and commensal bacteria, e.g. by E. coli K5. As a precursor in the biosynthesis of...
Heparosan is an acidic polysaccharide expressed as a capsule polymer by pathogenic and commensal bacteria, e.g. by E. coli K5. As a precursor in the biosynthesis of heparan sulfate and heparin, heparosan has a high biocompatibility and is thus of interest for pharmaceutical applications. However, due to its low immunogenicity, developing antibodies against heparosan and detecting the polymer in biological samples has been challenging. In this study, we exploited the enzyme repertoire of E. coli K5 and the E. coli K5-specific bacteriophage ΦK5B for the controlled synthesis and depolymerization of heparosan. A fluorescently labeled heparosan nonamer was used as a priming acceptor to study the elongation mechanism of the E. coli K5 heparosan polymerases KfiA and KfiC. We could demonstrate that the enzymes act in a distributive manner, producing labeled heparosan of low dispersity. The enzymatically synthesized heparosan was a useful tool to identify the tailspike protein KflB of ΦK5B as heparosan lyase and to characterize its endolytic depolymerization mechanism. Most importantly, using site-directed mutagenesis and rational construct design, we generated an inactive version of KflB for the detection of heparosan in ELISA-based assays, on blots, and on bacterial and mammalian cells.
Topics: Escherichia coli; Polymerization; Disaccharides; Polymers; Glycosyltransferases; Escherichia coli Proteins; N-Acetylglucosaminyltransferases
PubMed: 37567694
DOI: 10.1016/j.carbpol.2023.121182 -
Nanoscale Horizons Apr 2024Size-controlled drug delivery systems (DDSs) have gained significant attention in the field of pharmaceutical sciences due to their potential to enhance drug efficacy,... (Review)
Review
Size-controlled drug delivery systems (DDSs) have gained significant attention in the field of pharmaceutical sciences due to their potential to enhance drug efficacy, minimize side effects, and improve patient compliance. This review provides a concise overview of the preparation method, advancements, and applications of size-controlled drug delivery systems focusing on the sub-100 nm size DDSs. The importance of tailoring the size for achieving therapeutic goals is briefly mentioned. We highlight the concept of "template polymerization", a well-established method in covalent polymerization that offers precise control over molecular weight. We demonstrate the utility of this approach in crafting a monolayer of a polymer around biomolecule templates such as DNA, RNA, and protein, achieving the generation of DDSs with sizes ranging from several tens of nanometers. A few representative examples of small-size DDSs that share a conceptual similarity to "template polymerization" are also discussed. This review concludes by briefly discussing the drug release behaviors and the future prospects of "template polymerization" for the development of innovative size-controlled drug delivery systems, which promise to optimize drug delivery precision, efficacy, and safety.
Topics: Polymerization; Humans; Drug Delivery Systems; Drug Carriers; Particle Size; Polymers; Nanoparticles
PubMed: 38497369
DOI: 10.1039/d3nh00491k -
Journal of the American Chemical Society Apr 2024Controlling where and when self-assembly happens is crucial in both biological and synthetic systems as it optimizes the utilization of available resources. We...
Controlling where and when self-assembly happens is crucial in both biological and synthetic systems as it optimizes the utilization of available resources. We previously reported strictly seed-initiated linear crisscross polymerization with alternating recruitment of single-stranded DNA slats that are aligned in a parallel versus perpendicular orientation with respect to the double-helical axes. However, for some applications, it would be advantageous to produce growth that is faster than what a linear assembly can provide. Here, we implement crisscross polymerization with alternating sets of six parallel slats versus six perpendicular slats and use this framework to explore branching behavior. We present architectures that, respectively, are designed to exhibit primary, secondary, and hyperbranching growth. Thus, amplification via nonlinear crisscross polymerization can provide a route for applications such as low-cost, enzyme-free, and ultrasensitive detection.
Topics: DNA, Single-Stranded; Polymerization
PubMed: 38529625
DOI: 10.1021/jacs.4c00097 -
Biomacromolecules Aug 2023Well-defined, highly reactive poly(norbornenyl azlactone)s of controlled length (number-average degree of polymerization = 10 to 1,000) were made by ring-opening...
Well-defined, highly reactive poly(norbornenyl azlactone)s of controlled length (number-average degree of polymerization = 10 to 1,000) were made by ring-opening metathesis polymerization (ROMP) of pure -norbornenyl azlactone. These were converted into glycopolymers using a facile postpolymerization modification (PPM) strategy based on click aminolysis of azlactone side groups by amino-functionalized glycosides. Pegylated mannoside, heptyl-mannoside, and pegylated glucoside were used in the PPM. Binding inhibition of the resulting glycopolymers was evaluated against a lectin panel (Bc2L-A, FimH, langerin, DC-SIGN, ConA). Inhibition profiles depended on the sugars and the degrees of polymerization. Glycopolymers from pegylated-mannoside-functionalized polynorbornene, with = 100, showed strong binding inhibition, with subnanomolar range inhibitory concentrations (ICs). Polymers surpassed the inhibitory potential of their monovalent analogues by four to five orders of magnitude thanks to a multivalent (synergistic) effect. Sugar-functionalized poly(norbornenyl azlactone)s are therefore promising tools to study multivalent carbohydrate-lectin interactions and for applications against lectin-promoted bacterial/viral binding to host cells.
Topics: Mannose-Binding Lectins; Polymerization; Concanavalin A; Polymers; Polyethylene Glycols
PubMed: 37471408
DOI: 10.1021/acs.biomac.3c00406 -
Current Biology : CB Jan 2024In animals, cells often move as collectives to shape organs, close wounds, or-in the case of disease-metastasize. To accomplish this, cells need to generate force to...
In animals, cells often move as collectives to shape organs, close wounds, or-in the case of disease-metastasize. To accomplish this, cells need to generate force to propel themselves forward. The motility of singly migrating cells is driven largely by an interplay between Rho GTPase signaling and the actin network. Whether cells migrating as collectives use the same machinery for motility is unclear. Using the zebrafish posterior lateral line primordium as a model for collective cell migration, we find that active RhoA and myosin II cluster on the basal sides of the primordium cells and are required for primordium motility. Positive and negative feedbacks cause RhoA and myosin II activities to pulse. These pulses of RhoA signaling stimulate actin polymerization at the tip of the protrusions and myosin-II-dependent actin flow and protrusion retraction at the base of the protrusions and deform the basement membrane underneath the migrating primordium. This suggests that RhoA-induced actin flow on the basal sides of the cells constitutes the motor that pulls the primordium forward, a scenario that likely underlies collective migration in other contexts.
Topics: Animals; Actins; Zebrafish; Polymerization; Cell Movement; rhoA GTP-Binding Protein; Cytoskeletal Proteins; Myosin Type II
PubMed: 38096821
DOI: 10.1016/j.cub.2023.11.044 -
International Journal of Molecular... Jan 2024The low percentage of recyclability of the polymeric materials obtained by olefin transition metal (TM) polymerization catalysis has increased the interest in their... (Review)
Review
The low percentage of recyclability of the polymeric materials obtained by olefin transition metal (TM) polymerization catalysis has increased the interest in their substitution with more eco-friendly materials with reliable physical and mechanical properties. Among the variety of known biodegradable polymers, linear aliphatic polyesters produced by ring-opening polymerization (ROP) of cyclic esters occupy a prominent position. The polymer properties are highly dependent on the macromolecule microstructure, and the control of stereoselectivity is necessary for providing materials with precise and finely tuned properties. In this review, we aim to outline the main synthetic routes, the physical properties and also the applications of three commercially available biodegradable materials: Polylactic acid (PLA), Poly(Lactic--Glycolic Acid) (PLGA), and Poly(3-hydroxybutyrate) (P3HB), all of three easily accessible via ROP. In this framework, understanding the origin of enantioselectivity and the factors that determine it is then crucial for the development of materials with suitable thermal and mechanical properties.
Topics: Polymerization; Esters; Polyesters; Polymers; 3-Hydroxybutyric Acid
PubMed: 38338928
DOI: 10.3390/ijms25031647 -
Nature Chemistry Apr 2024Artificial cells are biomimetic microstructures that mimic functions of natural cells, can be applied as building blocks for molecular systems engineering, and host...
Artificial cells are biomimetic microstructures that mimic functions of natural cells, can be applied as building blocks for molecular systems engineering, and host synthetic biology pathways. Here we report enzymatically synthesized polymer-based artificial cells with the ability to express proteins. Artificial cells were synthesized using biocatalytic atom transfer radical polymerization-induced self-assembly, in which myoglobin synthesizes amphiphilic block co-polymers that self-assemble into structures such as micelles, worm-like micelles, polymersomes and giant unilamellar vesicles (GUVs). The GUVs encapsulate cargo during the polymerization, including enzymes, nanoparticles, microparticles, plasmids and cell lysate. The resulting artificial cells act as microreactors for enzymatic reactions and for osteoblast-inspired biomineralization. Moreover, they can express proteins such as a fluorescent protein and actin when fed with amino acids. Actin polymerizes in the vesicles and alters the artificial cells' internal structure by creating internal compartments. Thus, biocatalytic atom transfer radical polymerization-induced self-assembly-derived GUVs can mimic bacteria as they are composed of a microscopic reaction compartment that contains genetic information for protein expression upon induction.
Topics: Polymerization; Artificial Cells; Micelles; Actins; Polymers; Unilamellar Liposomes
PubMed: 38049652
DOI: 10.1038/s41557-023-01391-y -
European Journal of Medicinal Chemistry Jul 2023Gastrointestinal tumor is an important factor threatening human health. Natural product-based drug discovery is a popular paradigm for expanding the chemical space and...
Gastrointestinal tumor is an important factor threatening human health. Natural product-based drug discovery is a popular paradigm for expanding the chemical space and identifying new molecular entities that ameliorate human disease. Evodiamine-inspired medicinal chemistry presents therapeutic potential for treating tumors in different tissues via multi-target inhibition. Here, by focusing on the discovery of anti-gastrointestinal tumor drugs, a series of N(14) alkyl-substituted evodiamine derivatives were designed and synthesized. The structure-activity relationship studies culminated in the identification of the N(14)-propyl-substituted evodiamine analog 6b, which showed low nanomolar inhibitory activity against MGC-803 (IC = 0.09 μM) and RKO (IC = 0.2 μM) cell lines. Moreover, compound 6b was effective in inducing apoptosis, arresting the cell cycle in the G2/M phase, and inhibiting migration and invasion of MGC-803 and RKO cell lines in a dose-dependent manner in vitro. Further antitumor mechanism studies revealed that compound 6b significantly inhibited topoisomerase 1 (inhibition rate of 58.3% at 50 μM) and tubulin polymerization (IC = 5.69 μM). Overall, compound 6b represents a promising dual topoisomerase 1/tubulin-targeting lead structure for the treatment of gastrointestinal tumor.
Topics: Humans; Tubulin; Drug Screening Assays, Antitumor; Antineoplastic Agents; Structure-Activity Relationship; Apoptosis; Tubulin Modulators; Cell Line, Tumor; Cell Proliferation; Polymerization
PubMed: 37099835
DOI: 10.1016/j.ejmech.2023.115366 -
Bioelectrochemistry (Amsterdam,... Feb 2024Vitamin B being a natural catalyst in atom transfer radical polymerization (ATRP), has the advantages of mild reaction conditions, good biocompatibility and high...
Vitamin B being a natural catalyst in atom transfer radical polymerization (ATRP), has the advantages of mild reaction conditions, good biocompatibility and high catalytic efficiency. In this report, an electrochemical biosensor of the lung cancer biomarker microRNA-21 (miRNA-21) is designed for early screening of lung cancer with high sensitivity at the femtomolar level. In this approach, hairpin DNA with N end group was first attached to the electrode surface. When miRNA-21 was present and paired with hairpin DNA, the N group released and attached to the ATRP initiator through "click reaction". Through eATRP, a large number of FerrocenylMethyl Methacrylate (FcMMA) monomers polymerized into long chains for signal amplification. These long chains had a distinct electrical signal in the square wave voltammetry (SWV), which can detect RNA with high sensitivity. The limit of detection (LOD) goes down to 1.010 fM after ATRP polymerization, which is lower than that of the majority of other ultra-sensitive RNA electrochemical assays. Results also show that the vitamin B-based electrochemical biosensor is highly selective and suitable for RNA detection in complex biological samples.
Topics: Polymerization; Vitamin B 12; Electrochemical Techniques; DNA; Biosensing Techniques; Limit of Detection; Vitamins; MicroRNAs
PubMed: 37742523
DOI: 10.1016/j.bioelechem.2023.108578 -
Chemical Society Reviews Jun 2024Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with... (Review)
Review
Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with traditional drug-loaded nanocarriers in which drugs are just physically entrapped (, burst release, poor drug loadings). In the past few years, reversible-deactivation radical polymerization (RDRP) techniques have been extensively used to design tailor-made polymer prodrug nanocarriers. This synthesis strategy has received a lot of attention due to the possibility of fine tuning their structural parameters (, polymer nature and macromolecular characteristics, linker nature, physico-chemical properties, functionalization, ), to achieve optimized drug delivery and therapeutic efficacy. In particular, adjusting the nature of the drug-polymer linker has enabled the easy synthesis of stimuli-responsive polymer prodrugs for efficient spatiotemporal drug release. In this context, this review article will give an overview of the different stimuli-sensitive polymer prodrug structures designed by RDRP techniques, with a strong focus on the synthesis strategies, the macromolecular architectures and in particular the drug-polymer linker, which governs the drug release kinetics and eventually the therapeutic effect. Their biological evaluations will also be discussed.
Topics: Prodrugs; Polymerization; Drug Carriers; Humans; Polymers; Nanoparticles; Drug Liberation; Free Radicals
PubMed: 38775004
DOI: 10.1039/d2cs01060g