Selective inhibitors of trypanosomal uridylyl transferase RET1 establish druggability of RNA post-transcriptional modifications
Amy CordingMichael V. GormallyPeter J. BondMark CarringtonShankar BalasubramanianEric A. MiskaBeth Thomas
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Introduction Historically, therapeutic treatment of disease has been restricted to targeting proteins. Of the approximately 20,000 translated human proteins, approximately 1600 are associated with diseases. Strikingly, less than 15% of disease-associated proteins are predicted or known to be 'druggable.' While the concept and narrative of protein druggability continue to evolve with the development of novel technological and pharmacological advances, most of the human proteome remains undrugged. Recent genomic studies indicate that less than 2% of the human genome encodes for proteins, and while as much as 75% of the genome is transcribed, RNA has largely been ignored as a druggable target for therapeutic interventions.Areas covered This review delineates the theory and techniques involved in the development of small molecule inhibitors of RNAs from brute force, high-throughput screening technologies to de novo molecular design using computational machine and deep learning. We will also highlight the potential pitfalls and limitations of targeting RNA with small molecules.Expert opinion Although significant advances have recently been made in developing systems to identify small molecule inhibitors of RNAs, many challenges remain. Focusing on RNA structure and ligand binding sites may help bring drugging RNA in line with traditional protein drug targeting.
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We have previously described the posttranslational modification of pore-forming small proteins of Corynebacterium by mycolic acid, a very-long-chain α-alkyl and β-hydroxy fatty acid. Using a combination of chemical analyses and mass spectrometry, we identified the mycoloyl transferase (Myt) that catalyzes the transfer of the fatty acid residue to yield O-acylated polypeptides. Inactivation of corynomycoloyl transferase C (cg0413 [Corynebacterium glutamicum mytC {CgmytC}]), one of the six Cgmyt genes of C. glutamicum, specifically abolished the O-modification of the pore-forming proteins PorA and PorH, which is critical for their biological activity. Expectedly, complementation of the cg0413 mutant with either the wild-type gene or its orthologues from Corynebacterium diphtheriae and Rhodococcus, but not Nocardia, fully restored the O-acylation of the porins. Consistently, the three-dimensional structure of CgMytC showed the presence of a unique loop that is absent from enzymes that transfer mycoloyl residues onto both trehalose and the cell wall arabinogalactan. These data suggest the implication of this structure in the enzyme specificity for protein instead of carbohydrate.
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Білім берy қоғaмның экономикaлық дaмyының негізі, әлеyметтік тұрaқтылықтың фaкторлaрының бірі, хaлықтың рyхaни-aдaмгершілік әлеyетінің және интеллектyaлдық өсyінің қaйнaр көзі ретінде бaрлық yaқыттaрдa тaптырмaс құндылық болып есептеліп келеді. Aл қaзіргідей aдaм кaпитaлын қaлыптaстырy мен дaмытy мәселесін шешy негізгі міндет ретінде қaрaстырылaтын зaмaндa хaлықтың білімдік қaжеттіліктері өсіп, жоғaры, ортa aрнayлы, кәсіби қосымшa білім aлyғa үміткерлер сaны aртa түсyде. Бұғaн жayaп ретінде білім берy ұйымдaрының сaлaлaнyы aртып, әртүрлі типтегі оқy орындaрының сaны aртyдa, білім берyдің инфрaқұрылымы, бaсқaрy формaлaры, әдістемелік, ғылыми қызмет түрлері дaмyдa. Олaрды білім aлyшылaрдың жеке сұрaныстaры мен мүмкіндіктеріне бaғыттay күшейтілyде. Осығaн орaй білімнің сaпaсынa қойылaтын тaлaптaр aртып, бұл сaлaның әлеyметпен өзaрa әрекеттестігіне негізделген құрылымдық – қызметтік дaмyының көкейтестілігі aртyдa. Мaқaлaдa «серіктестік», «әлеyметтік серіктестік», «білімдегі әлеyметтік серіктестік» ұғым- дaрының мәні aшылып, олaрдың қaлыптaсy және дaмy үрдісіне шолy жaсaлaды, жоғaры оқy орындaрындa педaгогтaрды дaярлayдa әлеyметтік серіктестердің әлеyетін пaйдaлaнyдa бaсшылыққa aлынaтын ұстaнымдaр мен тиімді жолдaры сипaттaлaды. Түйін сөздер: серіктестік, әлеyметтік серіктестік, білімдегі әлеyметтік серіктестік, бірлескен әрекет ұстaнымдaры, әлеуметтік серіктестік әлеуеті. Обрaзовaние является основой экономического рaзвития обществa, одним из фaкторов социaль- ной стaбильности, источником дyховно-нрaвственного потенциaлa и интеллектyaльного ростa людей и во все временa считaлось незaменимой ценностью. И в нaстоящее время, когдa решение проблемы формировaния и рaзвития человеческого кaпитaлa рaссмaтривaется кaк основнaя зaдaчa, рaстyт обрaзовaтельные потребности людей, yвеличивaется количество желaющих полyчить высшее, среднее, специaльное, профессионaльное дополнительное обрaзовaние. В ответ нa это yсиливaется рaзветвленность обрaзовaтельных оргaнизaций, yвеличивaется количество обрaзовaтельных оргaни- зaций рaзличного типa, рaзвивaются инфрaстрyктyрa обрaзовaния, формы yпрaвления, методическaя и нayчнaя деятельность. Yсиливaется их ориентaция нa индивидyaльные потребности и возможности обyчaющихся. В связи с этим повышaются требовaния к кaчествy обрaзовaния, возрaстaет знaчение стрyктyрно-фyнкционaльного рaзвития этой сферы нa основе взaимодействия с обществом. В стaтье рaскрывaется знaчение понятий «пaртнерство», «социaльное пaртнерство», «социaльное пaртнерство в обрaзовaнии», рaссмaтривaется процесс их стaновления и рaзвития, описывaются рyко- водящие принципы и эффективные способы использовaния потенциaлa социaльных пaртнеров в подготовке педaгогических кaдров в высших yчебных зaведениях. Ключевые словa: партнерство, социaльное пaртнерство, социaльное пaртнерство в обрaзовaнии, принципы совместного действия, поненциал социального партнерство. Education is the basis of the economic development of society, one of the factors of social stability, a source of spiritual and moral potential and intellectual growth of people and has always been considered an irreplaceable value. And at the present time, when the solution of the problem of the formation and development of human capital is considered as the main task, the educational needs of people are growing, the number of people wishing to receive higher, secondary, special, professional additional education is increasing. In response to this, the branching of educational organizations is increasing, the number of educational organizations of various types is increasing, the infrastructure of education, forms of management, methodological and scientific activities are developing. Their focus on the individual needs and capabilities of students is increasing. In this regard, the requirements for the quality of education are increasing, the importance of the structural and functional development of this sphere on the basis of interaction with society is increasing. The article reveals the meaning of the concepts of "partnership", "social partnership", "social partnership in education", examines the process of their formation and development, describes the guidelines and effective ways to use the potential of social partners in the training of teachers in higher educational institutions. Keywords: partnership, social partnership, social partnership in education, principles of joint action, the potential of social partnership.
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Following sequencing and assembly of the human genome, the preferred methods for identification of new drug targets have changed dramatically. Modern tactics such as genome‐wide association studies (GWAS) and deep sequencing are fundamentally different from the pharmacology‐guided approaches used previously, in which knowledge of small molecule ligands acting at their cellular targets was the primary discovery engine. A consequence of the ‘target‐first, pharmacology‐second’ strategy is that many predicted drug targets are non‐enzymes, such as scaffolding, regulatory or structural proteins, and their activities are often dependent on protein–protein interactions (PPIs). These types of targets create unique challenges to drug discovery efforts because enzymatic turnover cannot be used as a convenient surrogate for compound potency. Moreover, it is often challenging to predict how ligand binding to non‐enzymes might affect changes in protein function and/or pathobiology. Thus, in the postgenomic era, targets might be strongly implicated by molecular biology‐based methods, yet they often later earn the designation of ‘undruggable’. Can the scope of available targets be widened to include these promising, but challenging, non‐enzymes? In this review, we discuss advances in high‐throughput screening (HTS) technology and chemical library design that are emerging to deal with these challenges.
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Leishmaniasis is a group of neglected infectious diseases, with approximately 1. 3 million new cases each year, for which the available therapies have serious limitations. Therefore, it is extremely important to apply efficient and low-cost methods capable of selecting the best therapeutic targets to speed up the development of new therapies against those diseases. Thus, we propose the use of integrated computational methods capable of evaluating the druggability of the predicted proteomes of Leishmania braziliensis and Leishmania infantum, species responsible for the different clinical manifestations of leishmaniasis in Brazil. The protein members of those proteomes were assessed based on their structural, chemical, and functional contexts applying methods that integrate data on molecular function, biological processes, subcellular localization, drug binding sites, druggability, and gene expression. These data were compared to those extracted from already known drug targets (BindingDB targets), which made it possible to evaluate Leishmania proteomes for their biological relevance and treatability. Through this methodology, we identified more than 100 proteins of each Leishmania species with druggability characteristics, and potential interaction with available drugs. Among those, 31 and 37 proteins of L. braziliensis and L. infantum, respectively, have never been tested as drug targets, and they have shown evidence of gene expression in the evolutionary stage of pharmacological interest. Also, some of those Leishmania targets showed an alignment similarity of <50% when compared to the human proteome, making these proteins pharmacologically attractive, as they present a reduced risk of side effects. The methodology used in this study also allowed the evaluation of opportunities for the repurposing of compounds as anti-leishmaniasis drugs, inferring potential interaction between Leishmania proteins and ~1,000 compounds, of which only 15 have already been tested as a treatment for leishmaniasis. Besides, a list of potential Leishmania targets to be tested using drugs described at BindingDB, such as the potential interaction of the DEAD box RNA helicase, TRYR, and PEPCK proteins with the Staurosporine compound, was made available to the public.
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Protein-protein interactions (PPIs) encompass a diverse range of molecular interfaces of high importance in biology. PPIs are classified as either obligate or transitory, although these perhaps represent two extremes of the spectrum. In 2005, the Wang group reported the structure-based design of spirooxindole-containing small molecules as a new class of potent small-molecule inhibitors of the murine double minute 2-p53 interaction. Structure-based or fragment-based drug design approaches have been particularly successful for protein systems where there is a good structural understanding of the key elements for recognition, affinity, and selectivity. The evidence so far demonstrates that finding bromodomain (BD) inhibitors outside of the BET family is achievable, whether in silico predictions deem the BDs to be difficult, intermediate, or druggable. The catalytic activity of many enzymes is modulated by PPIs, providing opportunities for drug discovery. Many protein complexes are dynamic, and pharmacological modulation can be achieved not only by PPI inhibition but also through their stabilization.
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Human proteome project
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