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991.
van Swieten PF Samuel E Hernández RO van den Nieuwendijk AM Leeuwenburgh MA van der Marel GA Kessler BM Overkleeft HS Kisselev AF 《Bioorganic & medicinal chemistry letters》2007,17(12):3402-3405
The ubiquitin-proteasome pathway degrades the majority of proteins in mammalian cells and plays an essential role in the generation of antigenic peptides presented by major histocompatibility class I molecules. Proteasome inhibitors are of great interest as research tools and drug candidates. Most work on proteasome inhibitors has focused on the inhibition of the chymotryptic-like (beta5) sites; little attention has been paid to the inhibition of two other types of active sites, the trypsin-like (beta2) and the caspase-like (beta1). We report here the development of the first cell-permeable and highly selective inhibitors (4 and 5) of the proteasome's caspase-like site. The selectivity of the compounds is directly and unambiguously established by Staudinger-Bertozzi labeling of proteasome subunits covalently modified with azide-functionalized inhibitor 5. This labeling reveals that the caspase-like site of the immunoproteasome (beta1i) is a preferred target of this compound. These compounds can be used as tools to study roles of beta1 and beta1i sites in generation of specific antigenic peptides and their potential role as co-targets of anti-cancer drugs. 相似文献
992.
Aaron Almeida David Chau Thomas Coolidge Hani El-Sabbahy Steven Hager Kevin Jose Masa Nakamura Alexei Voloshin 《Biotechnology progress》2022,38(2):e3227
Recent advancements in cell culture engineering have allowed drug manufacturers to achieve higher productivity by driving higher product titers through cell line engineering and high-cell densities. However, these advancements have shifted the burden to clarification and downstream processing where the difficulties now revolve around removing higher levels of process- and product-related impurities. As a result, a lot of research efforts have turned to developing new approaches and technologies or process optimization to still deliver high quality biological products while controlling cost of goods. Here, we explored the impact of a novel single use technology employing chromatographic principle-based clarification for a process-intensified cell line technology. In this study, a 16% economic benefit ($/g) was observed using a single-use chromatographic clarification compared to traditional single-use clarification technology by improving the overall product cost through decreased operational complexity, higher loading capacity, increased product recovery, and higher impurity clearance. In the end, the described novel chromatographic approach significantly simplified and enhanced the cell culture fluid harvest unit operation by combining the reduction of insoluble and key soluble contaminants of the harvest fluid into a single stage. 相似文献
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994.
Alexei A. Adzhubei Anastasia A. Anashkina 《Journal of biomolecular structure & dynamics》2017,35(12):2701-2713
Left-handed polyproline-II type helix is a regular conformation of polypeptide chain not only of fibrous, but also of folded and natively unfolded proteins and peptides. It is the only class of regular secondary structure substantially represented in non-fibrous proteins and peptides on a par with right-handed alpha-helix and beta-structure. In this study, we have shown that polyproline-II helix is abundant in several peptides and proteins involved in proteopathies, the amyloid-beta peptides, protein tau and prion protein. Polyproline-II helices form two interaction sites in the amyloid-beta peptides, which are pivotal for pathogenesis of Alzheimer’s disease (AD). It also with high probability is the structure of the majority of tau phosphorylation sites, important for tau hyperphosphorylation and formation of neurofibrillary tangles, a hallmark of AD. Polyproline-II helices form large parts of the structure of the folded domain of prion protein. They can undergo conversion to beta-structure as a result of relatively small change of one torsional angle of polypeptide chain. We hypothesize that in prions and amyloids, in general polyproline-II helices can serve as structural elements of the normal structure as well as dormant nuclei of structure conversion, and thus play important role in structure changes leading to the formation of fibrils. 相似文献
995.
Maria I. Kharitonova Alexandra O. Denisova Valeria L. Andronova Alexei L. Kayushin Irina D. Konstantinova Svetlana K. Kotovskaya Georgiy A. Galegov Valery N. Charushin Anatoly I. Miroshnikov 《Bioorganic & medicinal chemistry letters》2017,27(11):2484-2487
Using the enzymatic transglycosylation reaction β-d-ribo- and 2′-deoxyribofuranosides of 2-amino-5,6-difluorobenzimidazole nucleosides have been synthesized. 2-Amino-5,6-difluoro-benzimidazole riboside proved to exhibit a selective antiviral activity (selectivity index >32) against a wild strain of the herpes simplex virus type 1, as well as towards virus strains that are resistant to acyclovir, cidofovir, and foscarnet. We believe that this compound might be used for treatment of herpes infections in those cases, when acyclovir is not efficient. 相似文献
996.
Isatin‐induced increase in the affinity of human ferrochelatase and adrenodoxin reductase interaction 下载免费PDF全文
Pavel Ershov Yuri Mezentsev Andrey Gilep Sergey Usanov Olga Buneeva Alexei Medvedev Alexis Ivanov 《Protein science : a publication of the Protein Society》2017,26(12):2458-2462
Isatin (indol‐2,3‐dione) is an endogenous non‐peptide regulator exhibiting a wide range of biological and pharmacological activities, which are poorly characterized in terms of their molecular mechanisms. Identification of many isatin‐binding proteins in the mammalian brain and liver suggests that isatin may influence their functions. We have hypothesized that besides direct action on particular protein targets, isatin can act as a regulator of protein–protein interactions (PPIs). In this surface plasmon resonance‐based biosensor study we have found that physiologically relevant concentrations of isatin (25‐100 μM) increase affinity of interactions between human recombinant ferrochelatase (FECH) and NADPH‐dependent adrenodoxin reductase (ADR). In the presence of increasing concentrations of isatin the Kd values demonstrated a significant (up to 6‐fold) decrease. It is especially important that the interaction of isatin with each individual protein (FECH, ADR) was basically negligible and therefore could not contribute to the observed effect. This effect was specific only for the FECH/ADR complex formation and was not observed for other protein complexes studied: FECH/cytochrome b5(CYB5A) and FECH/SMAD4. 相似文献
997.
998.
999.
We simulated male gypsy moth flight phenology for the location of 1371 weather stations east of 100° W longitude and north
of 35° N latitude in North America. The output of these simulations, based on average weather conditions from 1961 to 1990,
was submitted to two map-interpolation methods: multiple regression and universal kriging. Multiple regression was found to
be as accurate as universal kriging and demands less computing power. A map of the date of peak male gypsy moth flight was
generated by universal kriging. This map itself constitutes a useful pest-management planning tool; in addition, the map delineates
the potential range of the gypsy moth based on its seasonality at the northern edge of its current distribution in eastern
North America. The simulation and map-interpolation methods described in this paper thus constitute an interesting approach
to the study and monitoring of the ecological impacts of climate change and shifts in land-use patterns at the sub-continental
level.
Received: 26 May 1998 / Accepted: 6 July 1998 相似文献
1000.
Florian Sure Marko Bertog Sara Afonso Alexei Diakov Ralf Rinke M. Gregor Madej Sabine Wittmann Thomas Gramberg Christoph Korbmacher Alexandr V. Ilyaskin 《The Journal of biological chemistry》2022,298(6)
The epithelial sodium channel (ENaC) is a heterotrimer consisting of α-, β-, and γ-subunits. Channel activation requires proteolytic release of inhibitory tracts from the extracellular domains of α-ENaC and γ-ENaC; however, the proteases involved in the removal of the γ-inhibitory tract remain unclear. In several epithelial tissues, ENaC is coexpressed with the transmembrane serine protease 2 (TMPRSS2). Here, we explored the effect of human TMPRSS2 on human αβγ-ENaC heterologously expressed in Xenopus laevis oocytes. We found that coexpression of TMPRSS2 stimulated ENaC-mediated whole-cell currents by approximately threefold, likely because of an increase in average channel open probability. Furthermore, TMPRSS2-dependent ENaC stimulation was not observed using a catalytically inactive TMPRSS2 mutant and was associated with fully cleaved γ-ENaC in the intracellular and cell surface protein fractions. This stimulatory effect of TMPRSS2 on ENaC was partially preserved when inhibiting its proteolytic activity at the cell surface using aprotinin but was abolished when the γ-inhibitory tract remained attached to its binding site following introduction of two cysteine residues (S155C–Q426C) to form a disulfide bridge. In addition, computer simulations and site-directed mutagenesis experiments indicated that TMPRSS2 can cleave γ-ENaC at sites both proximal and distal to the γ-inhibitory tract. This suggests a dual role of TMPRSS2 in the proteolytic release of the γ-inhibitory tract. Finally, we demonstrated that TMPRSS2 knockdown in cultured human airway epithelial cells (H441) reduced baseline proteolytic activation of endogenously expressed ENaC. Thus, we conclude that TMPRSS2 is likely to contribute to proteolytic ENaC activation in epithelial tissues in vivo. 相似文献