Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins.

Widespread adoption of mirror-image biological systems presents difficulties in accessing the requisite D-protein substrates. In particular, mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders with potentially unique recognition modes but is hindered by the individualized optimization required for D-protein chemical synthesis. We demonstrate a general mirror-image phage display pipeline that utilizes automated flow peptide synthesis to prepare D-proteins in a single run.

Binary combinatorial scanning reveals potent poly-alanine-substituted inhibitors of protein-protein interactions.

Establishing structure-activity relationships is crucial to understand and optimize the activity of peptide-based inhibitors of protein-protein interactions. Single alanine substitutions provide limited information on the residues that tolerate simultaneous modifications with retention of biological activity. To guide optimization of peptide binders, we use combinatorial peptide libraries of over 4,000 variants-in which each position is varied with either the wild-type residue or alanine-with a label-free affinity selection platform to study protein-ligand interactions.

Detecting the Knowledge Domains of Compound Semiconductors.

The development of compound semiconductors (CS) has received extensive attention worldwide. This study aimed to detect and visualize CS knowledge domains for quantifying CS research patterns and emerging trends through a scientometric review based on the literature between 2011 and 2020 by using . The combined dataset of 24,622 bibliographic records were collected through topic searches and citation expansion to ensure adequate coverage of the field.

Chelation-Tamoxifen Conjugates for Imaging of Estrogen Receptors.

The differential diagnosis of estrogen receptor-positive (ER+) pathway-activated systems by using a labeled antiestrogen helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. The authors' purpose was to synthesize chelator-tamoxifen conjugates for imaging ER (+) diseases. A hydroxypropyl linker was incorporated between either cyclam or cyclam diacetic acid and tamoxifen analog to produce SC-05-L-1 (Z-1-(1,4,8,11-tetraazacyclotetradecan-1-yl)-3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)propan-2-ol) and SC-05-N-1 (Z-2,2'-(4-(3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)-2-hydroxy-propyl)-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid), respectively.

A Hybrid Fuzzy Decision Model for Evaluating MEMS and IC Integration Technologies.

Integrated devices incorporating MEMS (microelectromechanical systems) with IC (integrated circuit) components have been becoming increasingly important in the era of IoT (Internet of Things). In this study, a hybrid fuzzy MCDM (multi-criteria decision making) model was proposed to effectively evaluate alternative technologies that incorporate MEMS with IC components. This model, composed of the fuzzy AHP (analytic hierarchy process) and fuzzy VIKOR (VIseKriterijumska Optimizacija I Kompromisno Resenje) methods, solves the decision problem of how best to rank MEMS and IC integration technologies in a fuzzy environment.

Discovery of High-Affinity Peptide Binders for the SARS-CoV-2 Spike Protein.

The β-coronavirus SARS-CoV-2 has caused a global pandemic. Affinity reagents targeting the SARS-CoV-2 spike protein are of interest for the development of therapeutics and diagnostics. We used affinity selection-mass spectrometry for the rapid discovery of synthetic high-affinity peptide binders for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein.

Does muscle improve validated outcome measures in open tibial fractures? New insights from a cohort study of the anterolateral thigh flap (ALT) versus ALT-Vastus lateralis flaps.

The benefits of the muscle in open lower limb fractures remain to be determined. This study compared statistically equivalent groups of open tibial fractures treated by free anterolateral thigh (ALT) flaps or ALT flaps incorporating muscle (ALT-Vastus lateralis/ALT- VL). Method and Results: Chang Gung Memorial Hospital, Taiwan, 2004-2008, 49 free flaps in open lower limb fractures (38 open tibial) were specifically reconstructed with free ALT or ALT-VL flaps.

A Platinum(IV) Prodrug-Perfluoroaryl Macrocyclic Peptide Conjugate Enhances Platinum Uptake in the Brain.

Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum(IV) prodrugs of cisplatin and perfluoroaryl peptide macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem-like cells.

A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus.

A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1'R,2'S) diastereomer displaying the highest GT1b inhibitory activity.

Ligand-Directed Divergent Synthesis of Carbo- and Heterocyclic Ring Systems.

Chemical tools that enable a catalytic reaction to selectively and efficiently yield different products will allow charting of wider chemical space. In ligand-directed divergent synthesis, a common mode of catalysis is modulated by employing different ligands for catalytic organometallic complexes to transform either common substrates or common reactive intermediates into distinct molecular scaffolds. The strategy has the potential to create important and diverse scaffolds and to unveil novel modes of catalytic transformations for wider synthetic applications.

A ligand-directed divergent catalytic approach to establish structural and functional scaffold diversity.

The selective transformation of different starting materials by different metal catalysts under individually optimized reaction conditions to structurally different intermediates and products is a powerful approach to generate diverse molecular scaffolds. In a more unified albeit synthetically challenging strategy, common starting materials would be exposed to a common metal catalysis, leading to a common intermediate and giving rise to different scaffolds by tuning the reactivity of the metal catalyst through different ligands. Herein we present a ligand-directed synthesis approach for the gold(I)-catalysed cycloisomerization of oxindole-derived 1,6-enynes that affords distinct molecular scaffolds following different catalytic reaction pathways.

A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide.

Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC = 0.92 nM).

Moderate to severe, but not mild, nonalcoholic fatty liver disease associated with increased risk of gallstone disease.

Objective: Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GSD) share some of the same risk factors. The association between NAFLD and GSD was inconsistent. Moreover, there are no studies on the association between GSD and the severity of NAFLD in the literature.

Anti-influenza drug discovery: identification of an orally bioavailable quinoline derivative through activity- and property-guided lead optimization.

From a high-throughput screening (HTS) hit with inhibitory activity against virus-induced cytophathic in the low micromolar range, we have developed a potent anti-influenza lead through careful optimization without compromising the drug-like properties of the compound. An orally bioavailable compound was identified as a lead agent with nanomolar activity against influenza, representing a 140-fold improvement over the initial hit.

Isatin-β-thiosemicarbazones as potent herpes simplex virus inhibitors.

A series of isatin-β-thiosemicarbazones have been designed and evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-β-thiosemicarbazone exhibited significant and selective antiviral activity with low cytotoxicity.

Synthesis, activity, and pharmacokinetic properties of a series of conformationally-restricted thiourea analogs as novel hepatitis C virus inhibitors.

A series of novel conformationally-restricted thiourea analogs were designed, synthesized, and evaluated for their anti-HCV activity. Herein we report the synthesis, structure-activity relationships (SARs), and pharmacokinetic properties of this new class of thiourea compounds that showed potent inhibitory activities against HCV in the cell-based subgenomic HCV replicon assay. Among compounds tested, the fluorene compound 4b was found to possess the most potent activity (EC(50)=0.

Design and efficient synthesis of novel arylthiourea derivatives as potent hepatitis C virus inhibitors.

A novel class of arylthiourea HCV inhibitors bearing various functionalities, such as cyclic urea, cyclic thiourea, urea, and thiourea, on the alkyl linker were designed and synthesized. Herein we report the synthesis and structure-activity relationships (SARs) of this novel class of arylthiourea derivatives that showed potent inhibitory activities against HCV in the cell-based subgenomic HCV replicon assay. Among compounds tested, the new carbazole derivative 64, which has an eight-carbon linkage between the phenyl and carbazole rings and a tolyl group at the N-9 position of carbazole, was found to possess strong anti-HCV activity (EC50=0.

Design and synthesis of indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives as novel HCV inhibitors.

An efficient synthetic methodology to provide indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives is described. These conformationally restricted heterobicyclic scaffolds were evaluated as a novel class of HCV inhibitors. Introduction of an acyl group at the NH(2) of the thiourea moiety has been found to enhance inhibitory activity.

Design, synthesis, and anti-HCV activity of thiourea compounds.

A series of thiourea derivatives were synthesized and their antiviral activity was evaluated in a cell-based HCV subgenomic replicon assay. SAR studies revealed that the chain length and the position of the alkyl linker largely influenced the in vitro anti-HCV activity of this class of potent antiviral agents. Among this series of compounds synthesized, the thiourea derivative with a six-carbon alkyl linker at the meta-position of the central phenyl ring (10) was identified as the most potent anti-HCV inhibitor (EC(50) = 0.

Stereocontrolled synthesis of polyfunctionalized cis-decalins from 2-methoxyphenols: total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane.

A four-step stereocontrolled synthesis of polyfunctionalized cis-decalins is described, involving oxidation of 2-methoxyphenol, intermolecular Diels-Alder reaction, olefination, and Cope rearrangement. Application of this efficient strategy to the total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane was accomplished from creosol and ethyl vinyl ketone via a common intermediate 21.

Synthesis and antipicornavirus activity of (R)- and (S)-1-[5-(4'-chlorobiphenyl-4-yloxy)-3-methylpentyl]-3-pyridin-4-yl-imidazolidin-2-one.

The new pyridyl imidazolidinone derivative, 1-[5-(4'-chlorobiphenyl-4-yloxy)-3-methylpentyl]-3-pyridin-4-yl-imidazolidin-2-one (+/-)-1a, was synthesized and found to have an excellent antiviral activity against EV71 (IC50 = 0.009 microM). Therefore, both the enantiomers, (S)-(+)-1a and (R)-(-)-1a, have been prepared starting from readily available monomethyl (R)-3-methylglutarate (7) as a useful chiral building block and their antiviral activity was evaluated in a plaque reduction assay.

Design, synthesis, and antipicornavirus activity of 1-[5-(4-arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives.

A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in markedly improved antiviral activity toward EV71 with IC(50) values of 5.0 nM (24b) and 9.