Probing Interfacial Behavior and Antifouling Activity of Adsorbed Copolymers at Solid/Liquid Interfaces.

Polymers containing poly(ethylene glycol) (PEG) units can exhibit excellent antifouling properties, which have been proposed/used for coating of biomedical implants, separation membranes, and structures in marine environments, as well as active ingredients in detergent formulations to avoid soil redepositioning in textile laundry. This study aimed to elucidate the molecular behavior of a copolymer poly(MMA-co-MPEGMA) containing antiadhesive PEG side chains and a backbone of poly(methyl methacrylate), at a buried polymer/solution interface. Polyethylene terephthalate (PET) was used as a substrate to model polyester textile surfaces. Sum frequency generation (SFG) vibrational spectroscopy was applied to examine the interfacial behavior of the copolymer at PET/solution interfaces in situ and in real time. Complementarily, copolymer adsorption on PET and subsequent antiadhesion against protein foulants were probed by quartz-crystal microbalance experiments with dissipation monitoring (QCM-D). Both applied techniques show that poly(MMA-co-MPEGMA) adsorbs significantly to the PET/solution interface at bulk polymer solution concentrations as low as 2 ppm, while saturation of the surface was reached at 20 ppm. The hydrophobic MMA segments provide an anchor for the copolymer to bind onto PET in an ordered way, while the pendant PEG segments are more disordered but contain ordered interfacial water. In the presence of considerable amounts of dissolved surfactants, poly(MMA-co-MPEGMA) could still effectively adsorb on the PET surface and remained stable at the surface upon washing with hot and cold water or surfactant solution. In addition, it was found that adsorbed poly(MMA-co-MPEGMA) provided the PET surface with antiadhesive properties and could prevent protein deposition, highlighting the superior surface affinity and antifouling performance of the copolymer. The results obtained in this work demonstrate that amphiphilic copolymers containing PMMA anchors and PEG side chains can be used in detergent formulations to modify polyester surfaces during laundry and reduce deposition of proteins (and likely also other soils) on the textile.

Antiadhesive Copolymers at Solid/Liquid Interfaces: Complementary Characterization of Polymer Adsorption and Protein Fouling by Sum Frequency Generation Vibrational Spectroscopy and Quartz-Crystal Microbalance Measurements with Dissipation Monitoring.

Amphiphilic copolymers comprising hydrophilic segments of poly(ethylene glycol) and hydrophobic domains that are able to adhere to solid/liquid interfaces have proven to be versatile ingredients in formulated products for various types of applications. Recently, we have reported the successful synthesis of a copolymer designed for modifying the surface properties of polyesters as mimics for synthetic textiles. Using sum frequency generation (SFG) spectroscopy, it was shown that the newly developed copolymer adsorbs effectively on the targeted substrates even in the presence of surfactants as supplied by common detergents. In the present work, these studies were extended to evaluate the ability of the formed copolymer adlayers to passivate polyester surfaces against undesired deposition of bio(macro)molecules, as represented by fibrinogen as model protein foulants. In addition, SFG spectroscopy was used to elucidate the structure of fibrinogen at the interface between polyester and water. To complement the obtained data with an independent technique, analogous experiments were performed using quartz-crystal microbalance with dissipation monitoring for the detection of the relevant interfacial processes. Both methods give consistent results and deliver a holistic picture of brush copolymer adsorption on polyester surfaces and subsequent antiadhesive effects against proteins under different conditions representing the targeted application in home care products.

Design and mechanism of tetrahydrothiophene-based γ-aminobutyric acid aminotransferase inactivators.

Low levels of γ-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of γ-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally restricted tetrahydrothiophene-based GABA analogues with a properly positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is 8 times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bonding interactions with Arg-192, a π-π interaction with Phe-189, and a weak nonbonded S···O═C interaction with Glu-270, thereby inactivating the enzyme.

Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase.

Two principal neurotransmitters are involved in the regulation of mammalian neuronal activity, namely, γ-aminobutyric acid (GABA), an inhibitory neurotransmitter, and L-glutamic acid, an excitatory neurotransmitter. Low GABA levels in the brain have been implicated in epilepsy and several other neurological diseases. Because of GABA's poor ability to cross the blood-brain barrier (BBB), a successful strategy to raise brain GABA concentrations is the use of a compound that does cross the BBB and inhibits or inactivates GABA aminotransferase (GABA-AT), the enzyme responsible for GABA catabolism. Vigabatrin, a mechanism-based inactivator of GABA-AT, is currently a successful therapeutic for epilepsy, but has harmful side effects, leaving a need for improved GABA-AT inactivators. Here, we report the synthesis and evaluation of a series of heteroaromatic GABA analogues as substrates of GABA-AT, which will be used as the basis for the design of novel enzyme inactivators.

Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers.

The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms: N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action, should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.