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ACS Central Science

Giulia Palermo, Yinglong Miao, Ross C Walker, Martin Jinek, J Andrew McCammon
The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system recently emerged as a transformative genome-editing technology that is innovating basic bioscience and applied medicine and biotechnology. The endonuclease Cas9 associates with a guide RNA to match and cleave complementary sequences in double stranded DNA, forming an RNA:DNA hybrid and a displaced non-target DNA strand. Although extensive structural studies are ongoing, the conformational dynamics of Cas9 and its interplay with the nucleic acids during association and DNA cleavage are largely unclear...
October 26, 2016: ACS Central Science
Jeffrey M Ting, Swapnil Tale, Anatolii A Purchel, Seamus D Jones, Lakmini Widanapathirana, Zachary P Tolstyka, Li Guo, Steven J Guillaudeu, Frank S Bates, Theresa M Reineke
Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin...
October 26, 2016: ACS Central Science
Parantap Sarkar, Zhe Sun, Toshiki Tokuhira, Motoko Kotani, Sota Sato, Hiroyuki Isobe
The stereochemistry of cycloarylene nanohoops gives rise to unique cyclostereoisomerism originating from hoop-shaped molecular shapes. However, cyclostereoisomerism has not been well understood despite the ever-increasing number of structural variants. The present work clarifies the cyclostereoisomerism of a cyclophenanthrenylene nanohoop possessing both E/Z- and R/S-geometries at the biaryl linkages. Involvement of the R/S axial chirality in the nanohoop leads to the deviation of the structure from a coplanar belt shape and allows for structural variations with 51 stereoisomers with E/Z- and R/S-geometries...
October 26, 2016: ACS Central Science
Joshua S Alford, Nadia C Abascal, Christopher R Shugrue, Sean M Colvin, David K Romney, Scott J Miller
A remarkable aspect of enzyme evolution is the portability of catalytic mechanisms for fundamentally different chemical reactions. For example, aspartyl proteases, which contain two active site carboxylic acid groups, catalyze the hydrolysis of amide bonds, while glycosyltransferases (and glycosyl hydrolases), which often also contain two active site carboxylates, have evolved to form (or break) glycosidic bonds. However, neither catalyst exhibits cross-reactivity in the intracellular environment. The large, macromolecular architectures of these biocatalysts tailor their active sites to their precise, divergent functions...
October 26, 2016: ACS Central Science
Jennifer N Wei, David Duvenaud, Alán Aspuru-Guzik
Reaction prediction remains one of the major challenges for organic chemistry and is a prerequisite for efficient synthetic planning. It is desirable to develop algorithms that, like humans, "learn" from being exposed to examples of the application of the rules of organic chemistry. We explore the use of neural networks for predicting reaction types, using a new reaction fingerprinting method. We combine this predictor with SMARTS transformations to build a system which, given a set of reagents and reactants, predicts the likely products...
October 26, 2016: ACS Central Science
Rashad R Karimov, Ankit Sharma, John F Hartwig
Selective functionalization of complex scaffolds is a promising approach to alter the pharmacological profiles of natural products and their derivatives. We report the site-selective azidation of benzylic and aliphatic C-H bonds in complex molecules catalyzed by the combination of Fe(OAc)2 and a PyBox ligand. The same system also catalyzes the trifluoromethyl azidation of olefins to form derivatives of natural products containing both fluorine atoms and azides. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity...
October 26, 2016: ACS Central Science
Miriam Cohen, Hooman P Senaati, Christopher J Fisher, Mia L Huang, Pascal Gagneux, Kamil Godula
Current drugs against the influenza A virus (IAV) act by inhibiting viral neuraminidase (NA) enzymes responsible for the release of budding virions from sialoglycans on infected cells. Here, we describe an approach focused on a search for inhibitors that reinforce the protective functions of mucosal barriers that trap viruses en route to the target cells. We have generated mimetics of sialo-glycoproteins that insert into the viral envelope to provide a well-defined mucus-like environment encapsulating the virus...
October 26, 2016: ACS Central Science
Wai Ling Cheung, Maria Y Chen, Mikhail O Maksimov, A James Link
Lasso peptides are a member of the superclass of ribosomally synthesized and posttranslationally modified peptides (RiPPs). Like all RiPPs, lasso peptides are derived from a gene-encoded precursor protein. The biosynthesis of lasso peptides requires two enzymatic activities: proteolytic cleavage between the leader peptide and the core peptide in the precursor protein, accomplished by the B enzymes, and ATP-dependent isopeptide bond formation, accomplished by the C enzymes. In a subset of lasso peptide biosynthetic gene clusters from Gram-positive organisms, the B enzyme is split between two proteins...
October 26, 2016: ACS Central Science
Alice E Williamson, Paul M Ylioja, Murray N Robertson, Yevgeniya Antonova-Koch, Vicky Avery, Jonathan B Baell, Harikrishna Batchu, Sanjay Batra, Jeremy N Burrows, Soumya Bhattacharyya, Felix Calderon, Susan A Charman, Julie Clark, Benigno Crespo, Matin Dean, Stefan L Debbert, Michael Delves, Adelaide S M Dennis, Frederik Deroose, Sandra Duffy, Sabine Fletcher, Guri Giaever, Irene Hallyburton, Francisco-Javier Gamo, Marinella Gebbia, R Kiplin Guy, Zoe Hungerford, Kiaran Kirk, Maria J Lafuente-Monasterio, Anna Lee, Stephan Meister, Corey Nislow, John P Overington, George Papadatos, Luc Patiny, James Pham, Stuart A Ralph, Andrea Ruecker, Eileen Ryan, Christopher Southan, Kumkum Srivastava, Chris Swain, Matthew J Tarnowski, Patrick Thomson, Peter Turner, Iain M Wallace, Timothy N C Wells, Karen White, Laura White, Paul Willis, Elizabeth A Winzeler, Sergio Wittlin, Matthew H Todd
The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change...
October 26, 2016: ACS Central Science
Liban M A Saleh, Rafal Dziedzic, Alexander M Spokoyny
No abstract text is available yet for this article.
October 26, 2016: ACS Central Science
Matthew I Gibson
No abstract text is available yet for this article.
October 26, 2016: ACS Central Science
Alla Katsnelson
No abstract text is available yet for this article.
October 26, 2016: ACS Central Science
Janet Pelley
No abstract text is available yet for this article.
October 26, 2016: ACS Central Science
Carolyn R Bertozzi
No abstract text is available yet for this article.
October 26, 2016: ACS Central Science
Catherine R Mulzer, Luxi Shen, Ryan P Bisbey, James R McKone, Na Zhang, Héctor D Abruña, William R Dichtel
The low conductivity of two-dimensional covalent organic frameworks (2D COFs), and most related coordination polymers, limits their applicability in optoelectronic and electrical energy storage (EES) devices. Although some networks exhibit promising conductivity, these examples generally lack structural versatility, one of the most attractive features of framework materials design. Here we enhance the electrical conductivity of a redox-active 2D COF film by electropolymerizing 3,4-ethylenedioxythiophene (EDOT) within its pores...
September 28, 2016: ACS Central Science
Joshua Lequieu, Andrés Córdoba, David C Schwartz, Juan J de Pablo
Nucleosomes form the basic unit of compaction within eukaryotic genomes, and their locations represent an important, yet poorly understood, mechanism of genetic regulation. Quantifying the strength of interactions within the nucleosome is a central problem in biophysics and is critical to understanding how nucleosome positions influence gene expression. By comparing to single-molecule experiments, we demonstrate that a coarse-grained molecular model of the nucleosome can reproduce key aspects of nucleosome unwrapping...
September 28, 2016: ACS Central Science
Tanja Krainz, Michael M Gaschler, Chaemin Lim, Joshua R Sacher, Brent R Stockwell, Peter Wipf
Discovering compounds and mechanisms for inhibiting ferroptosis, a form of regulated, nonapoptotic cell death, has been of great interest in recent years. In this study, we demonstrate the ability of XJB-5-131, JP4-039, and other nitroxide-based lipid peroxidation mitigators to prevent ferroptotic cell death in HT-1080, BJeLR, and panc-1 cells. Several analogues of the reactive oxygen species (ROS) scavengers XJB-5-131 and JP4-039 were synthesized to probe structure-activity relationships and the influence of subcellular localization on the potency of these novel ferroptosis suppressors...
September 28, 2016: ACS Central Science
D Matthew Peacock, Casey B Roos, John F Hartwig
We report a new class of catalytic reaction: the thermal substitution of a secondary and or tertiary alkyl halide with a nitrogen nucleophile. The alkylation of a nitrogen nucleophile with an alkyl halide is a classical method for the construction of C-N bonds, but traditional substitution reactions are challenging to achieve with a secondary and or tertiary alkyl electrophile due to competing elimination reactions. A catalytic process could address this limitation, but thermal, catalytic coupling of alkyl halides with a nitrogen nucleophile and any type of catalytic coupling of an unactivated tertiary alkyl halide with a nitrogen nucleophile are unknown...
September 28, 2016: ACS Central Science
Peng Dai, Chi Zhang, Matthew Welborn, James J Shepherd, Tianyu Zhu, Troy Van Voorhis, Bradley L Pentelute
Highly efficient and selective chemical reactions are desired. For small molecule chemistry, the reaction rate can be varied by changing the concentration, temperature, and solvent used. In contrast for large biomolecules, the reaction rate is difficult to modify by adjusting these variables because stringent biocompatible reaction conditions are required. Here we show that adding salts can change the rate constant over 4 orders of magnitude for an arylation bioconjugation reaction between a cysteine residue within a four-residue sequence (π-clamp) and a perfluoroaryl electrophile...
September 28, 2016: ACS Central Science
Eun Sil Jang, Jeremy M John, Richard R Schrock
Cis,syndiotacticA-alt-B copolymers, where A and B are two enantiomerically pure trans-2,3-disubstituted-5,6-norbornenes with "opposite" chiralities, can be prepared with stereogenic-at-metal initiators of the type M(NR)(CHR')(OR")(pyrrolide). Formation of a high percentage of alternating AB copolymer linkages relies on an inversion of chirality at the metal with each propagating step and a relatively fast formation of an AB sequence as a consequence of a preferred diastereomeric relationship between the chirality at the metal and the chirality of the monomer...
September 28, 2016: ACS Central Science
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