Micromirror Array with Adjustable Reflection Characteristics Based on Different Microstructures and Its Application.

The conventional reflective optical surface with adjustable reflection characteristics requires a complex external power source. The complicated structure and preparation process of the power system leads to the limited modulation of the reflective properties and difficulty of use in large-scale applications. Inspired by the biological compound eye, different microstructures are utilized to modulate the optical performance. Convex aspheric micromirror arrays (MMAs) can increase the luminance gain while expanding the field of view, with a luminance gain wide angle > 90° and a field-of-view wide angle close to 180°, which has the reflective characteristics of a large gain wide angle and a large field-of-view wide angle. Concave aspheric micromirror arrays can increase the luminance gain by a relatively large amount of up to 2.66, which has the reflective characteristics of high gain. Industrial-level production and practical applications in the projection display segment were carried out. The results confirmed that convex MMAs are able to realize luminance gain over a wide spectrum and a wide range of angles, and concave MMAs are able to substantially enhance luminance gain, which may provide new opportunities in developing advanced reflective optical surfaces.

Inhalable dry powder product (DPP) of mRNA lipid nanoparticles (LNPs) for pulmonary delivery.

Pulmonary delivery of mRNA via inhalation is a very attractive approach for RNA-based therapy for treatment of lung diseases. In this work, we have demonstrated successful development of an mRNA-lipid nanoparticle (LNP) dry powder product (DPP), wherein the LNPs were spray dried using hydroalcoholic solvent along with mannitol and leucine as excipients. The desired critical attributes for the DPP were accomplished by varying the excipients, lipid composition, concentration of LNPs, and weight percentage of mRNA. Leucine alone or in combination with mannitol improved the formulation by increasing the mRNA yield as well as decreasing the particle size. Intratracheal administration of the DPP in mice resulted in luciferase expression in the trachea and lungs indicating successful delivery of functional mRNA. Our results show formulation optimization of mRNA LNPs administered in the form of DPP results in an efficacious functional delivery with great promise for future development of mRNA therapeutics for lung diseases.

Superhydrophobic Multifocal Microlens Array with Depth-of-Field Detection for a Humid Environment.

Microlens array (MLA) has been widely applied in augmented reality and optical imaging. When used in a humid environment or medical endoscopy, MLA needs to be both superhydrophobic and multifocal. However, it is not easy to achieve both superhydrophobic and multifocal function by integrating superhydrophobic and multifocal structures on the same surface by means of a simple, efficient, and precise method. In this paper, the superhydrophobic multifocal MLA with superhydrophobic properties and multifocal functions is successfully designed for preparation based on a method of 3D lithography and soft lithography. The 3D lithography can further help the preparation of a multifocal MLA with varying apertures and a multistep superhydrophobic structure with a round dome. The superhydrophobic multifocal MLA with periods 50 and 120 µm has perfect superhydrophobic property. The water droplet can slide and bounce off the surface at a roll angle of less than 12.9° with both multifocal and integrated imaging function, as well as up to 397 µm depth-of-field (DOF) detection range; this greatly exceeds the conventional MLA. The perfect superhydrophobic and optical property can be achieved in an extremely humid environment. The superhydrophobic multifocal MLA proposed in this paper has a promising prospect for actual practices.

Artificial Hyper Compound Eyes Enable Variable-Focus Imaging on both Curved and Flat Surfaces.

The artificial compound eye (ACE) with zoom imaging requires complex power sources. Meanwhile, its curved substrate makes it difficult for the ACE to realize the zoom imaging on flat surfaces. To realize a wide field of view and a zoom function on both curved and flat surfaces simultaneously, a novel ACE is proposed, which is a bionic design inspired by an ancient creature, trilobite. Compared with a dragonfly, photosensitive units of a trilobite's compound eye are composed of ommatidia with different focal lengths. By learning from this concept, an artificial hyper compound eye (AHCE) was fabricated. Its basic components are five microlenses with different curvatures, and they are capable of being treated as five ommatidia with different focal lengths. Five ommatidia form a photosensitive unit to realize a zoom function. AHCE is capable of variable-focus imaging on curved surfaces. With the information share function, we found that the AHCE not only images on curved surfaces but also has a zoom-imaging function on flat surfaces. The results confirm that the AHCE demonstrates an advanced imaging capability, a variable-focus imaging function on both curved and flat surfaces, which may open new opportunities in developing advanced micro-optical devices.

Study on Poultry Pose Estimation Based on Multi-Parts Detection.

Poultry pose estimation is a prerequisite for evaluating abnormal behavior and disease prediction in poultry. Accurate pose-estimation enables poultry producers to better manage their poultry. Because chickens are group-fed, how to achieve automatic poultry pose recognition has become a problematic point for accurate monitoring in large-scale farms. To this end, based on computer vision technology, this paper uses a deep neural network (DNN) technique to estimate the posture of a single broiler chicken. This method compared the pose detection results with the Single Shot MultiBox Detector (SSD) algorithm, You Only Look Once (YOLOV3) algorithm, RetinaNet algorithm, and Faster_R-CNN algorithm. Preliminary tests show that the method proposed in this paper achieves a 0.0128 standard deviation of precision and 0.9218 ± 0.0048 of confidence (95%) and a 0.0266 standard deviation of recall and 0.8996 ± 0.0099 of confidence (95%). By successfully estimating the pose of broiler chickens, it is possible to facilitate the detection of abnormal behavior of poultry. Furthermore, the method can be further improved to increase the overall success rate of verification.

DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors.

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.

Author Correction: Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.

This corrects the article DOI: 10.1038/ncomms16081.

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors.

To identify BCATm inhibitors suitable for in vivo study, Encoded Library Technology (ELT) was used to affinity screen a 117 million member benzimidazole based DNA encoded library, which identified an inhibitor series with both biochemical and cellular activities. Subsequent SAR studies led to the discovery of a highly potent and selective compound, 1-(3-(5-bromothiophene-2-carboxamido)cyclohexyl)-N-methyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamide (8b) with much improved PK properties. X-ray structure revealed that 8b binds to the active site of BACTm in a unique mode via multiple H-bond and van der Waals interactions. After oral administration, 8b raised mouse blood levels of all three branched chain amino acids as a consequence of BCATm inhibition.

Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library.

As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 µM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.

The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors.

2',5'-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2',5'-oligoadenylate (2-5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2-5A. Phosphodiesterase 12 (PDE12) was the first cellular 2-5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2-5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2-5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity.

Discovery of Clinical Candidate GSK1842799 As a Selective S1P1 Receptor Agonist (Prodrug) for Multiple Sclerosis.

To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P1 modulators. One exemplar is (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol (10, GSK1842799). Upon phosphorylation, the compound (10-P) showed subnanomole S1P1 agonist activity with >1000× selectivity over S1P3. The alcohol 10 demonstrated good oral bioavailability and rapid in vivo conversion to 10-P. Dosed orally at 0.1 mg/kg, 10 significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, 10 achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of 10 at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound 10 (GSK1842799) was selected as a candidate for further clinical development.

Exploring amino acids derivatives as potent, selective, and direct agonists of sphingosine-1-phosphate receptor subtype-1.

In the quest to discover a potent and selective class of direct agonists to the sphingosine-1-phosphate receptor, we explored the carboxylate functional group as a replacement to previously reported lead phosphates. This has led to the discovery of potent and selective direct agonists with moderate to substantial in vivo lymphopenia. The previously reported selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) in the phenylamide and phenylimidazole scaffolds were crucial to obtaining selectivity for S1P receptor subtype 1 over 3.

Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT).

The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide (8), inhibited ADAMTS-5 with IC(50) = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds 8 and 15f inhibited aggrecanase-mediated (374)ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1ß/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.

Recent advances in the discovery and evaluation of fatty acid amide hydrolase inhibitors.

IMPORTANCE OF THE FIELD: Cannabis has been used for both medicinal and recreational purposes since ancient times. Although cannabinoid-based medicines hold great promise in several challenging therapeutic areas such as pain management and mode control, their development has been hampered by psychoactive and other CNS-related side effects. The identification of fatty acid amide hydrolase (FAAH), a key enzyme responsible for the degradation of endocannabinoids, has brought in tremendous opportunities in that inhibition of FAAH leads to local elevation of endocannabinoids under certain stimuli, thus, avoiding the side effects from global activation of cannabinoid receptors by exogenous cannabimimetic compounds. The search for selective FAAH inhibitors has thus become a strong focus in current drug discovery. AREAS COVERED IN THIS REVIEW: This review summarizes our current understanding of FAAH including its structure, catalytic mechanism and biological functions with emphases on its role in the regulation of endocannabinoids and other signaling lipids. The review then highlights the most recent discovery and biological activities of different classes of FAAH inhibitors. Last, the review discusses challenges and potential drawbacks in the development of FAAH inhibitor-based therapy. WHAT THE READER WILL GAIN: Readers will have an overview of FAAH and obtain a rationale on FAAH as an attractive therapeutic target for the development of medicines for treating pain, inflammation, anxiety and other diseases. More importantly, readers will gain knowledge on various newly established FAAH inhibitor scaffolds and their development potentials, and such information will hopefully stimulate ideas for the designing of new inhibitors with superior activity profiles. The discussions on the potential challenges in developing FAAH inhibitors will impose more caution in the decision-making process, thus, lowering the possibility of late stage failure. TAKE HOME MESSAGE: FAAH is an attractive target for modulating the endocannabinoid system, thus, treating many disease conditions including pain and mode control without the CNS side effects associated with cannabis usage. In recent years, tremendous effort has been focused in the FAAH inhibitor research field, and consequently many novel chemical templates have been discovered. FAAH hydrolyzes several important signaling lipids, but the long-term effects of FAAH inhibition in humans remain to be seen. While it is challenging to identify the right molecule with the right level of intervention of the FAAH function for treating a disease condition, it is possible to avoid mechanism-related undesired effects. With the entry of several compounds into clinical trials, FAAH inhibitor-based medicines are on the horizon.

Novel inhibitors of fatty acid amide hydrolase.

A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.

Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants.

Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.

Evaluation of the in vivo receptor occupancy for the behavioral effects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233.

G-protein coupled receptors exist in both high and low agonist affinity conformations, with tracer levels of agonist radioligands preferentially binding to the former. The goal of the present study was to characterize the in vivo binding of the aminoalkyindole-based, CB1 receptor agonist, R-[125/131I]AM2233 ((2-[125/131I]iodo-phenyl)-[1-(1-methyl-piperidin-2-yl-methyl)-1H-indol-3-yl]-methanone), and to use this radiotracer to selectively measure the receptor occupancy by the related CB1 receptor agonist, WIN55212-2, to the agonist-preferring affinity state of the receptor. In mouse locomotor assays, both WIN55212-2 and AM2233 (racemic) produced an approximately 60% reduction in activity at 1 mg/kg, (i.v.) and completely inhibited activity at 3 mg/kg, confirming their agonist nature. In ex vivo autoradiography, preferential uptake of R-[131I]AM2233 was apparent in CB1 receptor-rich areas, including globus pallidus, substantia nigra, striatum, cerebellum, and hippocampus. Overall brain uptake of R-[131I]AM2233 was 1.3% injected activity/g at 5 min in mice. Coinjection of 3 mg/kg (i.v.) SR141716A, a CB1 receptor antagonist, with R-[125I]AM2233 inhibited the radiotracer binding almost to nonspecific levels in the striatum, globus pallidus, and substantia nigra, although residual binding to a non-CB1 receptor remained in the hippocampus. In contrast to the effect of SR141716A, coinjection of 10 mg/kg (i.v.) WIN55212-2, a high dose that produced an immediate and profound immobility and catalepsy in the mice, reduced CB1 receptor-specific binding of R-[125I]AM2233 in CB1 receptor-rich areas by only 21-43%. These observations suggest that the behavioral effects of CB1 receptor agonists are manifested with a relatively small fraction of the agonist-preferring affinity state of the receptor occupied.

Synthesis, SAR exploration, and X-ray crystal structures of factor XIa inhibitors containing an alpha-ketothiazole arginine.

Using an alpha-ketothiazole arginine moiety as a key recognition element, a series of small peptidomimetic molecules was designed and synthesized, and their co-crystal structures with factor XIa were studied in an effort to develop smaller, less peptidic inhibitors as antithrombotic agents.

Potent cannabinergic indole analogues as radioiodinatable brain imaging agents for the CB1 cannabinoid receptor.

A series of novel aminoalkylindoles was synthesized in an effort to develop compounds that are potent agonists at the CB1 cannabinoid receptor and that are also easily labeled with radioisotopes of iodine for biochemical and imaging studies. 2-Iodophenyl-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]methanone (8, AM2233) had a very high affinity for the rat CB1 receptor, with most of the affinity residing with the (R)-enantiomer. Radioiodinated 8, (R)-8, and (S)-8 were prepared by radioiododestannylation of the tributyltin analogues in high yields, radiochemical purities, and specific radioactivities. In a mouse hippocampal membrane preparation with [131I](R)-8 as radioligand, racemic 8 exhibited a K(i) value of 0.2 nM compared with 1.6 nM for WIN55212-2. In autoradiographic experiments with mouse brain sections, the distribution of radioiodinated 8 was consistent with that of brain CB1 receptors. Again, very little specific binding was seen with the (S)-enantiomer [131I](S)-8 and none occurred with the (R)-enantiomer [131I](R)-8 in sections from CB1 receptor knockout mice. Radioiodinated 8 thus appears to be a suitable radioligand for studies of CB1 cannabinoid receptors.