Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation.

Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67-84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of 45 in complex with human BRD4 BD1 at a high resolution of 2.0 Å has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases.

Cinder: keeping crystallographers app-y.

The process of producing suitable crystals for X-ray diffraction analysis most often involves the setting up of hundreds (or thousands) of individual crystallization trials, each of which must be repeatedly examined for crystals or hints of crystallinity. Currently, the only real way to address this bottleneck is to use an automated imager to capture images of the trials. However, the images still need to be assessed for crystals or other outcomes. Ideally, there would exist some rapid and reliable machine-analysis tool to translate the images into a quantitative result. However, as yet no such tool exists in wide usage, despite this being a well recognized problem. One of the issues in creating robust automatic image-analysis software is the lack of reliable data for training machine-learning algorithms. Here, a mobile application, Cinder, has been developed which allows crystallization images to be scored quickly on a smartphone or tablet. The Cinder scores are inserted into the appropriate table in a crystallization database and are immediately available to the user through a more sophisticated web interface, allowing more detailed analyses. A sharp increase in the number of scored images was observed after Cinder was released, which in turn provides more data for training machine-learning tools.

Serial femtosecond crystallography: A revolution in structural biology.

Macromolecular crystallography at synchrotron sources has proven to be the most influential method within structural biology, producing thousands of structures since its inception. While its utility has been instrumental in progressing our knowledge of structures of molecules, it suffers from limitations such as the need for large, well-diffracting crystals, and radiation damage that can hamper native structural determination. The recent advent of X-ray free electron lasers (XFELs) and their implementation in the emerging field of serial femtosecond crystallography (SFX) has given rise to a remarkable expansion upon existing crystallographic constraints, allowing structural biologists access to previously restricted scientific territory. SFX relies on exceptionally brilliant, micro-focused X-ray pulses, which are femtoseconds in duration, to probe nano/micrometer sized crystals in a serial fashion. This results in data sets comprised of individual snapshots, each capturing Bragg diffraction of single crystals in random orientations prior to their subsequent destruction. Thus structural elucidation while avoiding radiation damage, even at room temperature, can now be achieved. This emerging field has cultivated new methods for nanocrystallogenesis, sample delivery, and data processing. Opportunities and challenges within SFX are reviewed herein.

Current advances in synchrotron radiation instrumentation for MX experiments.

Following pioneering work 40 years ago, synchrotron beamlines dedicated to macromolecular crystallography (MX) have improved in almost every aspect as instrumentation has evolved. Beam sizes and crystal dimensions are now on the single micron scale while data can be collected from proteins with molecular weights over 10 MDa and from crystals with unit cell dimensions over 1000 Å. Furthermore it is possible to collect a complete data set in seconds, and obtain the resulting structure in minutes. The impact of MX synchrotron beamlines and their evolution is reflected in their scientific output, and MX is now the method of choice for a variety of aims from ligand binding to structure determination of membrane proteins, viruses and ribosomes, resulting in a much deeper understanding of the machinery of life. A main driving force of beamline evolution have been advances in almost every aspect of the instrumentation comprising a synchrotron beamline. In this review we aim to provide an overview of the current status of instrumentation at modern MX experiments. The most critical optical components are discussed, as are aspects of endstation design, sample delivery, visualisation and positioning, the sample environment, beam shaping, detectors and data acquisition and processing.

Computational crystallization.

Crystallization is a key step in macromolecular structure determination by crystallography. While a robust theoretical treatment of the process is available, due to the complexity of the system, the experimental process is still largely one of trial and error. In this article, efforts in the field are discussed together with a theoretical underpinning using a solubility phase diagram. Prior knowledge has been used to develop tools that computationally predict the crystallization outcome and define mutational approaches that enhance the likelihood of crystallization. For the most part these tools are based on binary outcomes (crystal or no crystal), and the full information contained in an assembly of crystallization screening experiments is lost. The potential of this additional information is illustrated by examples where new biological knowledge can be obtained and where a target can be sub-categorized to predict which class of reagents provides the crystallization driving force. Computational analysis of crystallization requires complete and correctly formatted data. While massive crystallization screening efforts are under way, the data available from many of these studies are sparse. The potential for this data and the steps needed to realize this potential are discussed.

Current trends in protein crystallization.

UNLABELLED: Proteins belong to the most complex colloidal system in terms of their physicochemical properties, size and conformational-flexibility. This complexity contributes to their great sensitivity to any external change and dictate the uncertainty of crystallization. The need of 3D models to understand their functionality and interaction mechanisms with other neighbouring (macro)molecules has driven the tremendous effort put into the field of crystallography that has also permeated other fields trying to shed some light into reluctant-to-crystallize proteins. This review is aimed at revising protein crystallization from a regular-laboratory point of view. It is also devoted to highlight the latest developments and achievements to produce, identify and deliver high-quality protein crystals for XFEL, Micro-ED or neutron diffraction. The low likelihood of protein crystallization is rationalized by considering the intrinsic polypeptide nature (folded state, surface charge, etc) followed by a description of the standard crystallization methods (batch, vapour diffusion and counter-diffusion), including high throughput advances. Other methodologies aimed at determining protein features in solution (NMR, SAS, DLS) or to gather structural information from single particles such as Cryo-EM are also discussed. Finally, current approaches showing the convergence of different structural biology techniques and the cross-methodologies adaptation to tackle the most difficult problems, are presented. SYNOPSIS: Current advances in biomacromolecules crystallization, from nano crystals for XFEL and Micro-ED to large crystals for neutron diffraction, are covered with special emphasis in methodologies applicable at laboratory scale.

Hybrid materials science: a promised land for the integrative design of multifunctional materials.

For more than 5000 years, organic-inorganic composite materials created by men via skill and serendipity have been part of human culture and customs. The concept of "hybrid organic-inorganic" nanocomposites exploded in the second half of the 20th century with the expansion of the so-called "chimie douce" which led to many collaborations between a large set of chemists, physicists and biologists. Consequently, the scientific melting pot of these very different scientific communities created a new pluridisciplinary school of thought. Today, the tremendous effort of basic research performed in the last twenty years allows tailor-made multifunctional hybrid materials with perfect control over composition, structure and shape. Some of these hybrid materials have already entered the industrial market. Many tailor-made multiscale hybrids are increasingly impacting numerous fields of applications: optics, catalysis, energy, environment, nanomedicine, etc. In the present feature article, we emphasize several fundamental and applied aspects of the hybrid materials field: bioreplication, mesostructured thin films, Lego-like chemistry designed hybrid nanocomposites, and advanced hybrid materials for energy. Finally, a few commercial applications of hybrid materials will be presented.

Macromolecular self-assembly and nanotechnology in China.

Macromolecular self-assembly refers to the assembly of synthetic polymers, biomacromolecules and supra-molecular polymers. Through macromolecular self-assembly, the fabrication of ordered structures at different scales, the control of the dynamic assembly process and the integrations of advanced functions can be realized. Macromolecular self-assembly and nanotechnology research in China has developed rapidly, from the early periods of follow-up at low to high level and progress into a stage of innovation and creation. This review selects some representative progresses achieved recently, aiming to reflect the current status of macromolecular self-assembly and nanotechnology research in China.

The holistic 3M modality of drug delivery nanosystems for cancer therapy.

Cancer has become the leading cause of human death worldwide. There are many challenges in the treatment of cancer and the rapidly developing area of nanotechnology has shown great potential to open a new era in cancer therapy. This article, rather than being exhaustive, focuses on the striking progress in the drug delivery nanosystems (DDNS) for cancer therapy and selects typical examples to point out the emerging mode of action of DDNS from our perspective. Among the outstanding advances in DDNS for cancer therapy is the development of "multicomponent delivery systems", "multifunctional nanocarriers" and "multistage delivery systems". However, these represent only one aspect of DDNS research. In addition, nature is the best teacher and natural evolution pressure has meant that virions conform to the "multitarget, multistage and multicomponent" (3M) mode of action. Amazingly, traditional Chinese medicine (TCM), used for over 4000 years in China, also displays the same mode of action. Integrating the previous notable progress in nanoparticle technology, learned from the building mode of natural virions and the action concept of TCM, we propose an integrity-based 3M mode DDNS for cancer therapy: multitarget, multistage and multicomponent, which are not fragmented parts but an interconnected integrity. Based on the physiological multitarget and the pharmacokinetic multistage, multicomponent DDNS are rationally designed, where different components with individual specific functions act in a synergistic manner against each target at each disposition stage to maximize the targeted delivery effectiveness. In this article, we introduce each component of 3M DDNS in detail and describe some typical cases to realize the tumor-homing purposes.

Lipid-enveloped hybrid nanoparticles for drug delivery.

Recent advances in nanotechnology and material sciences have promoted the development of nanomedicine. Among the formulations developed, novel lipid-enveloped hybrid nanoparticles have attracted more attention because of their special structure, properties and clinical applicability. The hybrid nanoparticles are composed of a hydrophilic PEG shell, a nano-sized polymeric or inorganic core and a lipid mono- or bi-layer between the core and PEG shell. This kind of nanoparticle possesses both the characteristics of liposomes and nanoparticles which endows it with many advantages like long circulation, high drug loading efficiency, high stability and biocompatibility, controlled release properties, and drug cocktail delivery. This review describes the recent developments of lipid-enveloped hybrid nanoparticles in cancer treatment, including the fabrication methods, formulations and applications of these hybrid nanoparticles. We expect that the continuing development of lipid-based nanomedicine will greatly improve cancer treatment.

Recent developments in the study of opioid receptors.

It is now about 40 years since Avram Goldstein proposed the use of the stereoselectivity of opioid receptors to identify these receptors in neural membranes. In 2012, the crystal structures of the four members of the opioid receptor family were reported, providing a structural basis for understanding of critical features affecting the actions of opiate drugs. This minireview summarizes these recent developments in our understanding of opiate receptors. Receptor function is also influenced by amino acid substitutions in the protein sequence. Among opioid receptor genes, one polymorphism is much more frequent in human populations than the many others that have been found, but the functional significance of this single nucleotide polymorphism (SNP) has been unclear. Recent studies have shed new light on how this SNP might influence opioid receptor function. In this minireview, the functional significance of the most prevalent genetic polymorphism among the opioid receptor genes is also considered.

Light-directed nanosynthesis: near-field optical approaches to integration of the top-down and bottom-up fabrication paradigms.

The integration of top-down (lithographic) and bottom-up (synthetic chemical) methodologies remains a major goal in nanoscience. At larger length scales, light-directed chemical synthesis, first reported two decades ago, provides a model for this integration, by combining the spatial selectivity of photolithography with the synthetic utility of photochemistry. This review describes attempts to realise a similar integration at the nanoscale, by employing near-field optical probes to initiate selective chemical transformations in regions a few tens of nm in size. A combination of near-field exposure and an ultra-thin resist yields exceptional performance: in self-assembled monolayers, an ultimate resolution of 9 nm (ca. λ/30) has been achieved. A wide range of methodologies, based on monolayers of thiols, silanes and phosphonic acids, and thin films of nanoparticles and polymers, have been developed for use on metal and oxide surfaces, enabling the fabrication of metal nanowires, nanostructured polymers and nanopatterned oligonucleotides and proteins. Recently parallel lithography approaches have demonstrated the capacity to pattern macroscopic areas, and the ability to function under fluid, suggesting exciting possibilities for surface chemistry at the nanoscale.

Graphene: nanoscale processing and recent applications.

One of the most interesting features of graphene is the rich physics set up by the various nanostructures it may adopt. The planar structure of graphene makes this material ideal for patterning at the nanoscale. The breathtakingly fast evolution of research on graphene growth and preparation methods has made possible the preparation of samples with arbitrary sizes. Available sample production techniques, combined with the right patterning tools, can be used to tailor the graphene sheet into functional nanostructures, even whole electronic circuits. This paper is a review of the existing graphene patterning techniques and potential applications of related lithographic methods.

Multifunctional composite core-shell nanoparticles.

In this review paper, the state-of-the-art knowledge of the core-shell multifunctional nanoparticles (MNPs), especially with unique physiochemical properties, is presented. The synthesis methods were summarized from the aspects of both the advantages and the demerits. The core includes the inexpensive and easily oxidized metals and the noble shells include the relatively noble metals, carbon, silica, other oxides, and polymers. The properties including magnetic, optical, anti-corrosion and the surface chemistry of the NPs are thoroughly reviewed. The current status of the applications is reviewed with the detailed examples including the catalysis, giant magnetoresistance (GMR) sensing, electromagnetic interface shielding or microwave absorption, biomedical drug delivery, and the environmental remediation.

Surfactant-assisted, shape-controlled synthesis of gold nanocrystals.

The shape control of gold nanocrystals has attracted extensive research interest because of their unique shape-dependent properties and widespread applications. Surfactants have been frequently used in the shape-controlled synthesis of gold nanocrystals in solution. In this feature article, we summarize some of the emerging colloidal approaches towards shape-tailored gold nanocrystals with the assistance of surfactants, focusing on the roles played by surfactants in shape control. We start with a discussion on the general strategies in shape control of gold nanocrystals, which include adsorbate-directed synthesis, seed-mediated synthesis, template-assisted synthesis, and the control of growth kinetics. Then, we highlight some recent progress in the gold nanocrystal synthesis assisted by single surfactants, mixed surfactants, supramolecular surfactants, as well as metal-surfactant complex templates, which is followed by a brief description of the potential applications of shaped gold nanocrystals in catalysis and molecular sensing.

Supramolecular assembly/reassembly processes: molecular motors and dynamers operating at surfaces.

Among the many significant advances within the field of supramolecular chemistry over the past decades, the development of the so-called "dynamers" features a direct relevance to materials science. Defined as "combinatorial dynamic polymers", dynamers are constitutional dynamic systems and materials resulting from the application of the principles of supramolecular chemistry to polymer science. Like supramolecular materials in general, dynamers are reversible dynamic multifunctional architectures, capable of modifying their constitution by exchanging, recombining, incorporating components. They may exhibit a variety of novel properties and behave as adaptive materials. In this review we focus on the design of responsive switchable monolayers, i.e. monolayers capable to undergo significant changes in their physical or chemical properties as a result of external stimuli. Scanning tunneling microscopy studies provide direct evidence with a sub-nanometre resolution, on the formation and dynamic response of these self-assembled systems featuring controlled geometries and properties.