Inhibitory antibodies designed for matrix metalloproteinase modulation

The family of matrix metalloproteinases (MMPs) consists of a set of biological targets that are involved in a multitude of severe pathogenic events such as different forms of cancers or arthritis. Modulation of the target class with small molecule drugs has not led to the anticipated success until present, as all clinical trials failed due to unacceptable side effects or a lack of therapeutic outcome. Monoclonal antibodies offer a tremendous therapeutic potential given their high target selectivity and good pharmacokinetic profiles. For the treatment of a variety of diseases there are already antibody therapies available and the number is increasing. Recently, several antibodies were developed for the selective inhibition of single MMPs that showed high potency and were therefore investigated in in vivo studies with promising results. In this review, we highlight the progress that has been achieved toward the design of inhibitory antibodies that successfully modulate MMP-9 and MMP-14

Targeted fluoro positioning for the discovery of a potent and highly selective matrix metalloproteinase inhibitor

The incorporation of fluorine atoms into functional molecules is of wide interest in synthetic organic chemistry as well as cognate disciplines. In particular, in medicinal chemistry, there is a strong desire to positively influence the physicochemical molecular properties of drug compounds by introducing fluorine into biologically active molecules. Here, we present targeted fluoro positioning as the key design principle of converting a weak matrix metalloproteinase-13 (MMP-13 ) inhibitor into a very potent (IC50 = 6nM) and highly selective (selectivity factors of > 1000 over MMP-1, 2, 3, 7, 8, 9, 10, 12, 14) inhibitor with excellent plasma and microsomal stability, and no binding to the hERG channel (hERG: human ether-a-go-go related gene)

Strategic targeting of multiple water-mediated interactions : a concise and rational structure-based design approach to potent and selective MMP-13 inhibitors

Water in the architecture of life: Potent and selective matrix metalloproteinase-13 (MMP-13) inhibitors were rationally designed by targeting multiple water-mediated interactions between the target protein and small-molecule inhibitors. This structure-based design concept offers tremendous opportunities for the discovery of unique small molecules with tailored biological activity

Technostress Research: A Nurturing Ground for Measurement Pluralism?

Because technostress research is multidisciplinary in nature and, therefore, benefits from insights gained from various research disciplines, we expected a high degree of measurement pluralism in technostress studies published in the information systems (IS) literature. However, because IS research mostly relies on self-report measures in general, reasons exist to also assume that technostress research has largely neglected multi-method research designs. To assess the status quo of technostress research with respect to the application of multi-method approaches, we analyzed 103 empirical studies. Specifically, we analyzed the types of data-collection methods used and the investigated components of the technostress process (person, environment, stressors, strains, and coping). The results indicate that multi-method research is more prevalent in the IS technostress literature (approximately 37% of reviewed studies) than in the general IS literature (approximately 20% as reported in previous reviews). However, our findings also show that IS technostress studies significantly rely on self-report measures. We argue that technostress research constitutes a nurturing ground for the application of multi-method approaches and multidisciplinary collaboration

Molecular recognition of the catalytic zinc(II) ion in MMP-13 : structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies

Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91)

Sleep apnea-hypopnea quantification by cardiovascular data analysis

Sleep apnea is the most common sleep disturbance and it is an important risk factor for cardiovascular disorders. Its detection relies on a polysomnography, a combination of diverse exams. In order to detect changes due to sleep disturbances such as sleep apnea occurrences, without the need of combined recordings, we mainly analyze systolic blood pressure signals (maximal blood pressure value of each beat to beat interval). Nonstationarities in the data are uncovered by a segmentation procedure, which provides local quantities that are correlated to apnea-hypopnea events. Those quantities are the average length and average variance of stationary patches. By comparing them to an apnea score previously obtained by polysomnographic exams, we propose an apnea quantifier based on blood pressure signal. This furnishes an alternative procedure for the detection of apnea based on a single time series, with an accuracy of 82%

Heteroepitaxy of III–V Zinc Blende Semiconductors on Nanopatterned Substrates

In the last decade, zinc blende structure III–V semiconductors have been increasingly utilized for the realization of high‐performance optoelectronic applications because of their tunable bandgaps, high carrier mobility and the absence of piezoelectric fields. However, the integration of III–V devices on the Si platform commonly used for CMOS electronic circuits still poses a challenge, due to the large densities of mismatch‐related defects in heteroepitaxial III–V layers grown on planar Si substrates. A promising method to obtain thin III–V layers of high crystalline quality is the growth on nanopatterned substrates. In this approach, defects can be effectively eliminated by elastic lattice relaxation in three dimensions or confined close to the substrate interface by using aspect‐ratio trapping masks. As a result, an etch pit density as low as 3.3 × 105 cm−2 and a flat surface of submicron GaAs layers have been accomplished by growth onto a SiO2 nanohole film patterned Si(001) substrate, where the threading defects are trapped at the SiO2 mask sidewalls. An open issue that remains to be resolved is to gain a better understanding of the interplay between mask shape, growth conditions and formation of coalescence defects during mask overgrowth in order to achieve thin device quality III–V layers

The domain space of an analytic composition operator

In this paper we show that, for analytic composition operators between weighted Bergman spaces (including Hardy spaces) and as far as boundedness, compactness, order boundedness and certain summing properties of the adjoint are concerned, it is possible to modify domain spaces in a systematic fashion: there is a space of analytic functions which embeds continuously into each of the spaces under consideration and on which the above properties of the operator are decided. A remarkable consequence is that, in the setting of composition operators between weighted Bergman spaces, the properties in question can be identified as properties of the operator as a map between appropriately chosen Hilbert space