Interlayers Self-Generated by Additive-Metal Interactions in Organic Electronic Devices.

The fundamental structure of all organic electronic devices is a stack of thin layers sandwiched between electrodes, with precise intralayer morphology and interlayer interactions. Solution processing multilayers with little to no intermixing is, however, technically challenging and often incompatible with continuous roll-to-roll, high-speed manufacturing. Here, an overview of a recently developed methodology for self-generation of interlayers positioned between the active layer and metal contact is presented.

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention.

Dynamics of Additive Migration to Form Cathodic Interlayers in Organic Solar Cells.

Migration of additives to organic/metal interfaces can be used to self-generate interlayers in organic electronic devices. To generalize this approach for various additives, metals, and organic electronic devices it is first necessary to study the dynamics of additive migration from the bulk to the top organic/metal interface. In this study, we focus on a known cathode interlayer material, polyethylene glycol (PEG), as additive in P3HT:PCBM blends and study its migration to the blend/Al interface during metal deposition and its effect on organic solar cell (OSC) performance.

Flexible and stretchable power sources for wearable electronics.

Flexible and stretchable power sources represent a key technology for the realization of wearable electronics. Developing flexible and stretchable batteries with mechanical endurance that is on par with commercial standards and offer compliance while retaining safety remains a significant challenge. We present a unique approach that demonstrates mechanically robust, intrinsically safe silver-zinc batteries.

Screen printed passive components for flexible power electronics.

Additive and low-temperature printing processes enable the integration of diverse electronic devices, both power-supplying and power-consuming, on flexible substrates at low cost. Production of a complete electronic system from these devices, however, often requires power electronics to convert between the various operating voltages of the devices. Passive components-inductors, capacitors, and resistors-perform functions such as filtering, short-term energy storage, and voltage measurement, which are vital in power electronics and many other applications.

High Detectivity All-Printed Organic Photodiodes.

All-printed organic photodiode arrays on plastic are reported with average specific detectivities of 3.45 × 10(13) cm Hz(0.5) W(-1) at a bias of -5 V.

Chemical Composition of Additives That Spontaneously Form Cathode Interlayers in OPVs.

Interlayers between the active layer and the electrodes in organic devices are known to modify the electrode work function and enhance carrier extraction/injection, consequently improving device performance. It was recently demonstrated that chemical interactions between the evaporated electrode and interlayer additive can induce additive migration toward the metal/organic interface to spontaneously form the interlayer. In this work we used P3HT:PEG blends as a research platform to investigate the driving force for additive migration to the organic/metal interface and the source of the work function modification in OPVs.

Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution.

A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol.

A novel fluorogenic substrate for the measurement of endothelial lipase activity.

Endothelial lipase (EL) is a phospholipase A1 (PLA1) enzyme that hydrolyzes phospholipids at the sn-1 position to produce lysophospholipids and free fatty acids. Measurement of the PLA1 activity of EL is usually accomplished by the use of substrates that are also hydrolyzed by lipases in other subfamilies such as PLA2 enzymes. In order to distinguish PLA1 activity of EL from PLA2 enzymatic activity in cell-based assays, cell supernatants, and other nonhomogeneous systems, a novel fluorogenic substrate with selectivity toward PLA1 hydrolysis was conceived and characterized.

Potency variation of small-molecule chymase inhibitors across species.

Chymases (EC 3.4.21.

Structural basis for elastolytic substrate specificity in rodent alpha-chymases.

Divergence of substrate specificity within the context of a common structural framework represents an important mechanism by which new enzyme activity naturally evolves. We present enzymological and x-ray structural data for hamster chymase-2 (HAM2) that provides a detailed explanation for the unusual hydrolytic specificity of this rodent alpha-chymase. In enzymatic characterization, hamster chymase-1 (HAM1) showed typical chymase proteolytic activity.

Enhancing recombinant protein quality and yield by protein stability profiling.

The reliable production of large amounts of stable, high-quality proteins is a major challenge facing pharmaceutical protein biochemists, necessary for fulfilling demands from structural biology, for high-throughput screening, and for assay purposes throughout early discovery. One strategy for bypassing purification challenges in problematic systems is to engineer multiple forms of a particular protein to optimize expression, purification, and stability, often resulting in a nonphysiological sub-domain. An alternative strategy is to alter process conditions to maximize wild-type construct stability, based on a specific protein stability profile (PSP).

Protein engineering of the colony-stimulating factor-1 receptor kinase domain for structural studies.

A parallel approach to designing crystallization constructs for the c-FMS kinase domain was implemented, resulting in proteins suitable for structural studies. Sequence alignment and limited proteolysis were used to identify and eliminate unstructured and surface-exposed domains. A small library of chimeras was prepared in which the kinase insert domain of FMS was replaced with the kinase insert domain of previously crystallized receptor-tyrosine kinases.

Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.

The cFMS proto-oncogene encodes for the colony-stimulating factor-1 receptor, a receptor-tyrosine kinase responsible for the differentiation and maturation of certain macrophages. Upon binding its ligand colony-stimulating factor-1 cFMS autophosphorylates, dimerizes, and induces phosphorylation of downstream targets. We report the novel crystal structure of unphosphorylated cFMS in complex with two members of different classes of drug-like protein kinase inhibitors.

Dihydroquinone ansamycins: toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives.

Heat shock protein 90 (Hsp90) is critical for the maturation of numerous client proteins, many of which are involved in cellular transformation and oncogenesis. The ansamycins, geldanamycin (GA) and its derivative, 17-allylaminogeldanamycin (17-AAG), inhibit Hsp90. As such, the prototypical Hsp90 inhibitor, 17-AAG, has advanced into clinical oncology trials.

Effect of construct design on MAPKAP kinase-2 activity, thermodynamic stability and ligand-binding affinity.

MAPK-activated protein kinase-2 (MAPKAPK2) regulates the synthesis of tumor necrosis factor and other cytokines and is a potential drug target for inflammatory diseases. Five protein constructs were produced in 4-10mg quantities per liter of culture media using baculovirus-infected insect cells and characterized for kinase activity, thermal stability, and ligand-binding affinity. Compared to construct 1-370, removal of the C-terminal autoinhibitory peptide in 1-338 resulted in a destabilized but partially active nonphosphorylated enzyme; phosphorylation of 1-338 by p38alpha further increased activity 12-fold.

Discovery, SAR, and X-ray structure of novel biaryl-based dipeptidyl peptidase IV inhibitors.

The discovery, SAR, and X-ray crystal structure of novel biarylaminoacyl-(S)-2-cyano-pyrrolidines and biarylaminoacylthiazolidines as potent inhibitors of dipeptidyl peptidase IV (DPP IV) are reported.

Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells.

HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties.

Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.

A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions.

Structure-based design, synthesis and SAR of a novel series of thiopheneamidine urokinase plasminogen activator inhibitors.

The serine protease urokinase plasminogen activator (uPA) is thought to play a central role in tumor metastasis and angiogenesis. Molecular modeling studies suggest that 5-thiomethylthiopheneamidine inhibits uPA by binding at the S1 pocket of the active site. Further structure based elaboration of this residue resulted in a novel class of potent and selective inhibitors of uPA.

The 80's loop (residues 78 to 85) is important for the differential activity of retroviral proteases.

The abundance of structural data available for retroviral proteases affords a unique opportunity to investigate structure activity relationships. Our approach attempts to genetically engineer an HIV (human immunodeficiency virus)-1 protease that is functionally equivalent to the HIV-2 and the SIV (simian immunodeficiency virus) enzymes and conversely to engineer an HIV-2 protease that is functionally equivalent to the HIV-1 enzyme. For this purpose, the HIV-2 and SIV proteases were cloned and characterized in an Escherichia coli (E.

A heterologous substrate assay for the HIV-1 protease engineered in Escherichia coli.

A heterologous substrate assay for the human immunodeficiency virus type 1 (HIV-1) protease has been engineered in Escherichia coli. This assay detects the activity of the HIV-1 protease within intact bacterial cells and does not require biochemical purification of either the enzyme or the substrate. For this assay, nine HIV-1 protease specificity sites were genetically engineered into a heterologous protein (galactokinase) and the relative processing of these substrates by the wild-type and a substituted HIV-1 protease was determined.

Stimulation of the herpes simplex virus type I protease by antichaeotrophic salts.

The herpes simplex virus type 1 protease is expressed as an 80,000-dalton polypeptide, encoded within the 635-amino acid open reading frame of the UL26 gene. The two known protein substrates for this enzyme are the protease itself and the capsid assembly protein ICP35 (Liu, F., and Roizman, B.

The protease of herpes simplex virus type 1 is essential for functional capsid formation and viral growth.

The herpes simplex virus type 1 protease and related proteins are involved in the assembly of viral capsids. The protease encoded by the UL26 gene can process itself and its substrate ICP35, encoded by the UL26.5 gene.

Investigation of the specificity of the herpes simplex virus type 1 protease by point mutagenesis of the autoproteolysis sites.

The herpes simplex virus type 1 (HSV-1) protease is cleaved at two autoprocessing sites during viral maturation, one of which shares amino acid identity with its substrate, ICP35. Similar autoprocessing sites have been observed within other members of the Herpesviridae. Introduction of point mutations within the autoprocessing sites of the HSV-1 protease indicated that specificity resides within the P4-P1' region of the cleavage sites.