Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design

The development of protein-protein interaction (PPI) inhibitors with therapeutic value is of increasing importance as the first clinical agent has now been approved, but PPIs remain difficult targets for the development of small molecule ligands. This article describes a highly efficient approach to the development of inhibitors of the p53/hDMX or hDM2 interaction that involves the design of small molecules in silico based upon a peptide/protein structure. The process for molecule design, starting from a virtual library of just over 1200 fragments, led to the eventual synthesis of twenty compounds, of which ten bound to either hDM2, hDMX or both in vitro binding assays. This 50% success rate is extremely efficient compared to traditional high throughput screening. The identification of two selective hDMX inhibitors from twenty compounds highlights this efficiency as, to date, only two other hDMX-selective agents exist in the literature. Preliminary biological studies show that 20% of the compounds identified have cellular activity and activate downstream pathways associated with p53 activation

One-Year Treatment With Exenatide Improves β-Cell Function, Compared With Insulin Glargine, in Metformin-Treated Type 2 Diabetic Patients: A randomized, controlled trial

0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS: Exenatide significantly improves beta-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, beta-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therap

Stereocontrolled protein surface recognition using chiral oligoamide proteomimetic foldamers

The development of foldamers capable of selective molecular recognition of solvent exposed protein surfaces represents an outstanding challenge in supramolecular chemical biology. Here we introduce an oligoamide foldamer with well-defined conformation that bears all the hallmarks of an information rich oligomer. Specifically, the foldamer recognizes its target protein hDM2 leading to inhibition of its protein–protein interaction with p53 in a manner that depends upon the composition, spatial projection and stereochemistry of functional groups appended to the scaffold. Most significantly, selective inhibition of p53/hDM2 can be achieved against four other targets and the selectivity for p53/hDM2 inhibition versus Mcl-1/NOXA-B inhibition is critically dependent upon the stereochemistry of the helix mimetic

Proteflazid: the specific activity against the hepatitis C virus in preclinical studies; efficacy and safety in the treatment of hepatitis B and C in clinical practice (systematic review)

В систематическом обзоре литературы показана специфическая активность препарата Протефлазид в отношении вируса гепатита С в условиях доклинического изучения. Подтверждена безопасность и эффективность применения препаратов Протефлазид (капли) и Флавозид® (сироп) в клинической практике при лечении гепатитов В и С у детей (175 больных) и взрослых (846 больных, в том числе 262 беременных). Результаты независимых исследований совпадают и свидетельствуют об эффективности и безопасности применения указанных препаратов; A systematic review of the literature shows the specific activity of Proteflazid against the virus of hepatitis С in a pre-clinical study. Confirmed the safety and effectiveness of medications Proteflazid (drops) and Flavozid® (syrup), in clinical practice in the treatment of hepatitis В and С among children (175) and adults (846 patients, including 262 рregnancy cases). The results of independent research and demonstrated the effectiveness and safety of drugs Proteflazid

Multivalent helix mimetics for PPI-inhibition.

The exploitation of multivalent ligands for the inhibition of protein-protein interactions has not yet been explored as a supramolecular design strategy. This is despite the fact that protein-protein interactions typically occur within the context of multi-protein complexes and frequently exploit avidity effects or co-operative binding interactions to achieve high affinity interactions. In this paper we describe preliminary studies on the use of a multivalent N-alkylated aromatic oligoamide helix mimetic for inhibition of p53/hDM2 and establish that protein dimerisation is promoted, rather than enhanced binding resulting from a higher effective concentration of the ligand. This journal i

Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

Synthesis of Highly Functionalized Oligobenzamide Proteomimetic Foldamers by Late Stage Introduction of Sensitive Groups

α-Helix proteomimetics represent an emerging class of ligands that can be used to inhibit an array of helix mediated protein-protein interactions. Within this class of inhibitor, aromatic oligobenzamide foldamers have been widely and succssefuly used. This manuscript describes alternative syntheses of these compounds that can be used to access mimetics that are challenging to synthesize using previously described methodologies, permiting access to compounds functionalized with multiple sensitive side chains and accelerated library assembly through late stage derivatisation

Hypoglycemia Detection in Diabetes

Hypoglycemia, once detected in a timely manner, is commonly treated by administration of glucose or glucagon in accordance with HCP advice, however, identifying the hypoglycemic event or need to treat is of initial paramount importance. The definition of hypoglycemia is provided, together with the implications of such an event on clinical and economic outcomes. The current accuracy standards are discussed and how they are applied to the low blood glucose range and current technologies

Personal features of women-active users of social networks

Объектом исследования являются психологические особенности интернет-пользователей. Предметом исследования стали личностные особенности женщин-активных пользователей социальных сетей. Магистерская диссертация состоит из введения, двух глав, заключения, списка литературы (172 источника) и приложения, включающего в себя бланки применявшихся методик, сводную таблицу данных, описательные статистики. Объем магистерской диссертации 123 страницы, на которых размещены 8 рисунков и 7 таблиц. Во введении раскрывается актуальность проблемы исследования, теоретическая и практическая значимость работы. разработанность проблематики, ставятся цель и задачи исследования, определяются объект и предмет исследования, формулируются основные гипотезы, указываются методы и эмпирическая база, а также этапы проведения исследования. В первой главе рассматривалась теоретическая база таких изучаемых явлений, как интернет-зависимость, проблемное использование интернета, проводился теоретический анализ исследований посвящённых связи активности пользователей социальных сетей с их личностными особенностями. В частности был проведён обзор исследований, посвящённых личностным особенностям женщин с высокой активностью в социальных сетях. Выводы по первой главе представляют собой итоги по изучению теоретического материала. Вторая глава посвящена эмпирической части исследования. В ней представлено описание организации и методов проведенного исследования и результатов, полученных по всем использованным методикам: «Общая шкала проблемного использования интернета» (GPIUS3), «Краткий опросник Большая пятерка» (адаптация А.Б.Хромова и др), Методика «уровень субъективного контроля» Дж.Роттера. Также в главе представлен сравнительный и корреляционный анализ результатов исследования. Выводы по главе 2 включают в себя основные результаты эмпирического исследования. В заключении в обобщенном виде изложены результаты теоретической и эмпирической частей работы, а также выводы по выдвинутым гипотезам, обоснована практическая значимость исследования и описаны возможные перспективы дальнейшей разработки данной проблематики.The object of the research is the Psychological features of Internet users. The subject of the research was the personal features of women active users of social networks. The master's thesis consists of an introduction, two chapters, a conclusion, a list of references (172 sources) and an appendix, which includes the forms of the methods used, a summary table of data, descriptive statistics. The volume of the master's thesis is 123 pages, which contain 8 figures and 7 tables. The introduction reveals the relevance of the research problem, the theoretical and practical significance of the work. the elaboration of the problematics, the goal and objectives of the research are set, the object and subject of the research are determined, the main hypotheses are formulated, the methods and empirical base, as well as the stages of the research, are indicated. In the first chapter, the theoretical basis of such studied phenomena as Internet addiction, problematic use of the Internet was considered, a theoretical analysis of studies devoted to the connection between the activity of users of social networks and their personal characteristics was carried out. In particular, a review of studies on the personal characteristics of women with high activity in social networks was carried out. Conclusions on the first chapter are the results of the study of theoretical material. The second chapter is devoted to the empirical part of the study. It contains a description of the organization and methods of the study and the results obtained by all the methods used: "General scale of problematic Internet use" (GPIUS3), "Brief questionnaire Big Five" (adaptation by A. Khromov and others), Methodology "level of subjective control" J. Rotter. The chapter also provides a comparative and correlation analysis of the research results. The findings of Chapter 2 are the main results of the empirical study. In conclusion, brief results of the theoretical and empirical parts of the work are presented, as well as conclusions on the hypotheses. The practical significance of the study is substantiated and possible prospects for further development of the problematics are described