Optimization and preclinical evaluation of novel histamine H3 receptor ligands: Acetyl and propionyl phenoxyalkyl piperazine derivatives

As a continuation of our search for novel histamine H₃ receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2–25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H₃ receptors (hH₃R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH₃R affinity (hH₃R K_i?=?5.2–115?nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH₃R K_i?=?5.2 and 15.4?nM vs. 10.2 and 115?nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed.     

Analysis of the long-term stability of the output of electron beams generated by the Novac11™ IORT accelerator

Aim

The aim of the study was to analyze the long-term stability of electron beams generated by the Novac11? IORT accelerator.

Stabilization of mesophilic Allochromatium vinosum cytochrome c′ through specific mutations modeled by a thermophilic homologue

AVCP cytochrome c′ from mesophilic Allochromatium vinosum exhibits lower stability than a thermophilic counterpart, Hydrogenophilus thermoluteolus cytochrome c′ (PHCP), in which the six specific amino acid residues that are not conserved in AVCP are responsible for its stability. Here we measured the stability of AVCP variants carrying these specific residues instead of the original AVCP ones. Among the six single AVCP variants, all of which formed a dimeric structure similar to that of the wild-type, three were successfully stabilized compared with the wild-type, while one showed lower stability than the wild-type. In addition, the most stabilized and destabilized AVCP variants could bind CO, similar to the wild-type. These results indicated that mesophilic AVCP could be stabilized through specific three mutations modeled by the thermophilic counterpart, PHCP, without changing the CO binding ability.     

Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.     

ProtaBank: A repository for protein design and engineering data

We present ProtaBank, a repository for storing, querying, analyzing, and sharing protein design and engineering data in an actively maintained and updated database. ProtaBank provides a format to describe and compare all types of protein mutational data, spanning a wide range of properties and techniques. It features a user‐friendly web interface and programming layer that streamlines data deposition and allows for batch input and queries. The database schema design incorporates a standard format for reporting protein sequences and experimental data that facilitates comparison of results across different data sets. A suite of analysis and visualization tools are provided to facilitate discovery, to guide future designs, and to benchmark and train new predictive tools and algorithms. ProtaBank will provide a valuable resource to the protein engineering community by storing and safeguarding newly generated data, allowing for fast searching and identification of relevant data from the existing literature, and exploring correlations between disparate data sets. ProtaBank invites researchers to contribute data to the database to make it accessible for search and analysis. ProtaBank is available at https://protabank.org .     

Fused‐Ring Electron Acceptor ITIC‐Th: A Novel Stabilizer for Halide Perovskite Precursor Solution

Solution‐processed perovskite solar cells have great potential for low‐cost roll‐to‐roll fabrication. However, the degradation of aged precursor solutions will become a critical obstacle to mass production. In this report, a small molecule (ITIC‐Th) is employed to stabilize the perovskite precursor solution containing mixed cations and halides. It is found that ITIC‐Th can effectively suppress the formation of yellow δ‐phase in the films made from aged precursor solutions. Consequently, the devices fabricated from the aged precursor solution with ITIC‐Th experience much less efficiency drop with the increase of the precursor aging time—from 19.20% (fresh) to 16.55% (39 d), compared with the devices made from conventional precursor solutions dropping from 18.07% (fresh) to 1.76% (39 d). The characterizations suggest that ITIC‐Th is beneficial for CH₃NH₃⁺ cations to be incorporated into the crystal structure, facilitating the formation of perovskite phase. Furthermore, the presence of ITIC‐Th in the perovskite thin film gives rise to additional photocurrent as well as improved fill factor due to the well‐matched energy levels, the passivation of defects, and the complementary absorption spectra, suggesting a new route toward future high‐efficiency solar cells—incorporating organic non‐fullerene acceptors and halide perovskite materials into the same active layer.     

Thermodynamically Self‐Healing 1D–3D Hybrid Perovskite Solar Cells

Thermal degradation in perovskite solar cells is still an unsettled issue that limits its further development. In this study, 2‐(1H‐pyrazol‐1‐yl)pyridine is introduced into lead halide 3D perovskites, which allows 1D–3D hybrid perovskite materials to be obtained. The heterostructural 1D–3D perovskites are proved to be capable of remarkably prolonging the photoluminescence decay lifetime and suppressing charge carrier recombination in comparison to conventional 3D perovskites. The intrinsic properties of thermodynamically stable yet kinetically labile 1D materials allow the system to alleviate the lattice mismatch and passivate the interface traps of heterojunction region of 1D–3D hybrid perovskites that may occur during the crystal growth process. Importantly, the as‐fabricated 1D–3D perovskite solar cells display a thermodynamic self‐healing ability, which is induced through blocking the ion‐migration channels of A‐site ions by the flexible 1D perovskite with less densely close‐packed structure. Particularly, the power conversion efficiency of as‐fabricated unencapsulated 1D–3D perovskite solar cells is demonstrated to be reversible under temperature cycling (25–85 °C) at 55% relative humidity, which largely outperforms the pure 3D perovskite solar cell. The present study provides a facile approach to fabricate 1D–3D perovskite solar cells with high efficiency and long‐term stability.