The Interaction Between Gamma-Secretase And Its Inhibitors And Modulators – Structural Insights

Gamma-secretase is a four subunit, 20-pass transmembrane aspartyl protease that has sustained a great deal of scientific scrutiny due to its role in disease: Gamma-secretase cleaves amyloid precursor protein, catalyzing the formation of amyloid plaques, which contribute to Alzheimer’s disease (AD) pathogenesis, and it also cleaves Notch, the abnormal signaling of which can lead to cancer. Gamma-secretase has been reported to process over 90 other substrates, all of which are type 1 transmembrane proteins. As a result of gamma-secretase’s enzymatic promiscuity and role in many pivotal cellular processes, it is a difficult target for drug development. Gamma-secretase inhibitors (GSIs), which pan-inhibit gamma-secretase so that it cannot cleave any of its substrates, are poor candidates for AD therapy as they cause toxicity. Still, GSIs are promising candidates for cancer. Gamma-secretase modulators (GSMs), which reduce formation of the amyloidogenic A?42 without affecting Notch signaling, are promising therapeutics for AD, as they avoid the Notch-associated toxicities seen with GSI treatment. In order to develop safe and effective therapies for AD and cancer we must gain a deeper understanding of gamma-secretase biology and the mechanism of action of GSIs/GSMs. To understand the process of gamma-secretase activation we developed CBAP-BPyne, a clickable photoaffinity probe that inhibits not only gamma-secretase activity, but also endoproteolysis, an event required for formation of an active gamma-secretase complex. We found that CBAP-BPyne specifically labels PS1-NTF and signal peptide peptidase (SPP). Endoproteolysis is not well characterized and CBAP-BPyne is a valuable tool with which to further explore its mechanism. To provide insight into the mechanism of action of GSIs/GSMs, we studied the impact of these compounds on the active sites of their target enzyme, gamma-secretase, and on an off-target enzyme, SPP. We found that GSIs/GSMs impact the active site architecture of not only gamma-secretase, but also SPP, suggesting that they may lead to a change in SPP activity and function, potentially causing toxicity in the clinic. Furthermore, we identified the binding site of BMS-708163, a clinically relevant GSI, on gamma-secretase, marking the first time that a GSI/GSM was mapped onto its target with high precision

γ-secretase inhibitors and modulators induce distinct conformational changes in the active sites of γ-secretase and signal peptide peptidase

γ-Secretase inhibitors (GSIs) and modulators (GSMs) are at the frontline of cancer and Alzheimer’s disease research, respectively. While both are therapeutically promising, not much is known about their interactions with proteins other than γ-secretase. Signal peptide peptidase (SPP), like γ-secretase, is a multispan transmembrane aspartyl protease that catalyzes regulated intramembrane proteolysis. We used active site-directed photophore walking probes to study the effects of different GSIs and GSMs on the active sites of γ-secretase and SPP and found that nontransition state GSIs inhibit labeling of γ-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of GSMs, which have little effect on the labeling of γ-secretase but diminish labeling of SPP. These results demonstrate that GSIs and GSMs are altering the structure of not only γ-secretase but also SPP, leading to potential changes in enzyme activity and specificity that may impact the clinical outcomes of these molecules

Estimating the potential risks of developing clusters in medical industry using various ranking criteria

Objective to develop methodology for risk assessment of functioning of the medical industry companies as cluster members. Methods methods of financial management of enterprises in the field of risk management were used. Results by the example of the selected industry the interaction of hightech enterprises in a cluster and risks arising therein are shown. The need to improve competitiveness of the Russian medical devices manufacturers and medical institutions on the one hand and their integration into global production chains on the other hand requires taking into account international risk management experience. The risk assessment algorithm for the medical industry companiesrsquo formation and functioning in a cluster structure is given based on selected indicators of probable risks and levels of the companiesrsquo development or maturity. It is shown that ranking of the technological and economic risks of cluster companiesrsquo development within the complex of measures of financial and economic analysis aimed at minimizing the negative impact of internal and external environment may improve the organizational and economic sustainability of enterprises and organizations participating in the cluster. At the same time business processes determined by the cluster membersrsquo interaction should include mechanisms of not only minimizing but also of excluding and in case of impossibility ndash insuring the risks. Investigation of the economic entitiesrsquo stability should be carried out with the methods of economic and financial analysis. It is shown that risk minimization is possible through the use of methods of financial and economic analysis which allow estimating with varying degrees of reliability the probability of cluster development risks associated with its organizational and economic stability. Scientific novelty the article presents a model of cluster membersrsquo interaction determining the place of the controlling module as a link that collects and analyzes information from all enterprises and organizations of the cluster processes it in a convenient form for interpretation and represents it to the management module for making decisions on risk management. Practical significance the proposed approach to risk assessment and the formation of a controlling system can be used in the practice of clusters in the field of medicine for making managerial decisions and improving the efficiency of interactionbetween medical companies and medical institutions

Роль высших учебных заведений России и Китая в развитии инновационных образовательных кластеров

The article is devoted to one of the most perspective mechanisms of innovation implementation in Russia and China – in the form of innovation educational clusters. The leading role of higher educational institutions is underlined in formation of innovative economy and high-tech projects, as well as in the decision of previously established and newly emerging constraints associated with global processes in the world economy. Based on the review and analysis of its results, the authors formulate proposals for applying the existing experience of implementing the cluster approach with the direct participation of higher education institutions in the creation of international innovative educational clusters for the formation of joint projects in the most promising industries and technologies, in particular, in the medical industry and pharmaceuticals. The relevance of the research is due to the need for further development of educational and scientific ties, trade and economic relations between Russia and China, increasing the competitiveness of both national economic systems as a whole, and high-tech enterprises of the two countries in domestic and global markets.Статья посвящена одному из наиболее перспективных механизмов внедрения инноваций в России и Китае – инновационным образовательным кластерам. Подчеркивается ведущая роль высших учебных заведений в формировании инновационной экономики и реализации высокотехнологичных проектов, а также в решении уже сформировавшихся ранее и недавно возникших ограничений, связанных с глобальными процессами в мировой экономике. На основании проведенного обзора и анализа его результатов, автор формулирует предложения по применению уже существующего опыта реализации кластерного подхода при непосредственном участии высших учебных заведений в создании международных инновационных образовательных кластеров для формирования совместных проектов в наиболее перспективных отраслях, в частности, в медицинской промышленности и фармацевтике. Актуальность исследования обусловлена необходимостью дальнейшего развития образовательных и научных связей, торгово-экономических отношений России и Китая, повышении конкурентоспособности как национальных экономических систем в  целом, так и высокотехнологичных предприятий двух стран на внутренних и на мировом рынка

Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules

Gamma-secretase is a membrane-bound aspartyl-protease that cleaves many membrane substrates including Amyloid Precursor Protein (APP), Notch, E-cadherin, Her4 and CD44. APP is a particularly notable substrate because of its association with Alzheimer disease. Together, gamma-secretase and beta-secretase cleave APP to produce amyloid beta peptides that aggregate in the brain as cytotoxic beta-amlyoid plaques, which is one of the hallmarks of Alzheimer disease. Many small molecules are being developed to target gamma-secretase as a therapeutic strategy for Alzheimer disease. However, studying the effects of these molecules on the active site conformation of gamma-secretase is challenging due to the complexity of this enzyme. In our study, we have developed new biochemical techniques to probe the active site structure of gamma-secretase. We are able to show that different gamma-secretase inhibitors and modulators, when bind to gamma-secretase, affect the active site structure of gamma-secretase differently. More importantly, we discovered that these small molecules, which were developed to target gamma-secretase, also affect the active site structure of Signal Peptide Peptidase, a similar membrane-bound aspartyl-protease. This discovery has major implication on the development of gamma-secretase inhibitors as therapeutic drugs for Alzheimer disease due to potential off-target effects

Повышение конкурентоспособности российских вузов и роль государственных программ в развитии высшего образования

The project aimed to increase the competitiveness of Russian universities among the world’s leading research and educational centers, which was called “5–100”, was completed in 2020. The aim of this project assumed the entry of five Russian universities into the TOP 100 world institutional rankings. However, due to the fact that there are currently a large number of international rankings among higher education institutions, both global and industry-specific or subject-specific, the indicators achieved within the framework of the “5–100” project are still being discussed by the expert community. For the further effective implementation of the national project “Science“ in terms of achieving the priority state development goals in the field of science and education, it is important to formulate proposals and mechanisms for realization the strategic academic leadership program” Priority-2030“ on the basis of available data and the results of the analysis of the experience gained, which are presented in this paper.Проект повышения конкурентоспособности российских университетов среди ведущих мировых научно-образовательных центров, получивший название «5–100», завершился в 2020 г. Результатом проекта должно было стать вхождение пяти отечественных вузов в топ-100 мировых институциональных рейтингов. Однако, в силу того что среди высших учебных заведений в настоящее время существует большое количество международных рейтингов как глобальных, так и отраслевых или предметных, достигнутые в рамках проекта «5–100» показатели обсуждаются экспертным сообществом до сих пор. Для дальнейшей эффективной реализации национального проекта «Наука» в части достижения приоритетных целей развития государства в области науки и образования представляется важным сформулировать предложения и механизмы реализации программы стратегического академического лидерства «Приоритет-2030» на основе имеющихся данных и результатов анализа полученного опыта, которые и будут представлены в данной работе

ω-3 Fatty acids for major depressive disorder in adults: an abridged Cochrane review.

OBJECTIVE: To assess the effects of n-3 polyunsaturated fatty acids (n-3PUFAs; also known as ω-3 fatty acids) compared with comparator for major depressive disorder (MDD) in adults. DESIGN: Systematic review and meta-analyses. DATA SOURCES: The Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Registers (CCDANCTR) and International Trial Registries searched to May 2015. CINAHL searched to September 2013. TRIAL SELECTION: INCLUSION CRITERIA: a randomised controlled trial (RCT); that provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and was conducted in adults with MDD. OUTCOMES: Primary outcomes were depressive symptomology and adverse events. RESULTS: 20 trials encompassing 26 relevant studies were found. For n-3PUFAs versus placebo, n-3PUFA supplementation resulted in a small-to-modest benefit for depressive symptomology: SMD=-0.32 (95% CI -0.52 to -0.12; 25 studies, 1373 participants, very low-quality evidence), but this effect is unlikely to be clinically meaningful, is very imprecise and, based on funnel plot inspection, sensitivity analyses and comparison with large well-conducted trials, is likely to be biased. Considerable evidence of heterogeneity between studies was also found, and was not explained by subgroup or sensitivity analyses. Numbers of individuals experiencing adverse events were similar in intervention and placebo groups (OR=1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence). For n-3PUFAs versus antidepressants, no differences were found between treatments in depressive symptomology (MD=-0.70 (95% CI -5.88 to 4.48); 1 study, 40 participants, very low-quality evidence). CONCLUSIONS: At present, we do not have sufficient evidence to determine the effects of n-3PUFAs as a treatment for MDD. Further research in the form of adequately powered RCTs is needed

A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients

We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4–20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions—Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort