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In a phase 2 trial of iberdomide in patients with moderate-to-severe SLE, a composite response (on the Systemic Lupus Erythematosus Responder Index–4) occurred in 54% of those who received iberdomide (0.45 mg), as compared with 35% in the placebo group, but this between-group difference was not significant at lower doses. Urinary tract and respiratory tract infections and neutropenia occurred.

Background and Objective Gemigliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor used in the treatment of type 2 diabetes mellitus. This study evaluated possible pharmacodynamic and pharmacokinetic interactions between gemigliptin and metformin and investigated their tolerability. Methods A randomized, open-label, multiple-dose, three-treatment, three-period, three-sequence crossover study was conducted in healthy male subjects. Twenty-seven subjects received gemigliptin (50 mg once daily), metformin (1,000 mg twice a day), or both drugs for 7 days per dosing period. Blood samples were drawn over 24 h on the seventh day of each period for pharmacokinetic and pharmacodynamic evaluations, including plasma DPP-4 activity and total/active glucagon-like peptide-1 (GLP-1) levels. Meal tolerance tests were conducted for pharmacodynamic assessment on the eighth day. Safety and tolerability were evaluated using adverse events, vital signs, ECGs, and clinical laboratory tests. Results Coadministration of gemigliptin and metformin had no significant effect on the pharmacokinetics of gemigliptin or metformin. The inhibition of DPP-4 by gemigliptin was not affected by coadministration with metformin. Co-therapy of gemigliptin and metformin showed additional effects by increasing plasma active GLP-1 concentrations and lowering serum glucose levels. The plasma glucagon level was lower in co-therapy than with metformin monotherapy. The coadministration of gemigliptin and metformin was well-tolerated without serious adverse events. Conclusions Coadministration of gemigliptin and metformin showed beneficial anti-diabetic effects without pharmacokinetic drug–drug interactions.

Purpose Gemigliptin is approved for the treatment of type II diabetes mellitus. Sulfonylureas are commonly used in combination with other antidiabetic drugs to improve glycemic control. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of gemigliptin and glimepiride combination therapy compared with those of monotherapies. Methods A randomized, open-label, crossover study was performed on healthy Korean male volunteers. Each subject received the following treatments (A and B) with a 7-day washout period: treatment A consisted of gemigliptin 50 mg once daily administered orally for 6 days, followed by concomitant oral dosing of glimepiride 4 mg and gemigliptin 50 mg on day 7; treatment B consisted of a single dose of glimepiride 4 mg. Blood samples were collected up to 24-h postdose on day 6 (gemigliptin) and day 7 (gemigliptin and glimepiride) following treatment A, and on day 1 (glimepiride) following treatment B. Concentrations of gemigliptin, glimepiride, and metabolites were determined using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS). Safety assessments were performed throughout the study. Results Twenty-three subjects completed the study. The geometric mean ratios (GMRs) of C max,ss and AUC τ ,ss for gemigliptin were 1.0097 [90 % confidence interval (CI) 0.924–1.103] and 0.9997 (90 % CI 0.976–1.024), respectively. For glimepiride, the GMRs of C max and AUC last were 1.031 (90 % CI 0.908–1.172) and 0.995 (90 % CI 0.902–1.097), respectively. Both combination and monotherapy were well tolerated, and no serious adverse events were reported. Conclusion Gemigliptin and glimepiride did not alter the pharmacokinetic properties of each other when they were co-administered in healthy volunteers, and were generally tolerated.

Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed a small interfering RNA (siRNA) screen to identify those interactors that have functional roles in authentic LASV infection. As proof of principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small-molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet-to-be-defined host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.

Fascin an anticancer target Analogues of the natural product migrastatin are potent inhibitors of tumour cell migration and metastasis. In this study, Lin Chen et al . elucidate the mechanism involved and show that these migrastatin analogues target and inhibit the activity of the actin bundling protein, fascin. These results suggest that actin cytoskeletal proteins, such as fascin, may present new molecular targets for cancer treatment. Analogues of migrastatin — a natural product secreted by Streptomyces — are potent inhibitors of tumour cell migration and metastasis. Here, the underlying mechanism is elucidated: these migrastatin analogues target and inhibit the activity of the actin-bundling protein fascin. Hence proteins such as fascin might present new molecular targets for cancer treatments. Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces 1 , 2 , and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis 3 , 4 , 5 , 6 . Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

The ribosome is a molecular machine responsible for protein synthesis and a major target for small-molecule inhibitors. Compared to the wealth of structural information available on ribosome-targeting antibiotics in bacteria, our understanding of the binding mode of ribosome inhibitors in eukaryotes is currently limited. Here we used X-ray crystallography to determine 16 high-resolution structures of 80S ribosomes from Saccharomyces cerevisiae in complexes with 12 eukaryote-specific and 4 broad-spectrum inhibitors. All inhibitors were found associated with messenger RNA and transfer RNA binding sites. In combination with kinetic experiments, the structures suggest a model for the action of cycloheximide and lactimidomycin, which explains why lactimidomycin, the larger compound, specifically targets the first elongation cycle. The study defines common principles of targeting and resistance, provides insights into translation inhibitor mode of action and reveals the structural determinants responsible for species selectivity which could guide future drug development. Whereas previous structural investigation of ribosome inhibitors has been done using the prokaryotic ribosome, this work presents X-ray crystal structures of the yeast ribosome in complex with 16 inhibitors including eukaryotic-specific inhibitors; the inhibitors all bind the mRNA or tRNA binding sites, larger molecules appear to target specifically the first elongation cycle. Mechanisms of eukaryotic ribosome inhibition As the ribosome is a common target of antibiotics, there is a wealth of structural data on the binding of the bacterial ribosome to various inhibitors. Our understanding of inhibitor binding to the larger eukaryotic ribosome is limited. Marat Yusupov and colleagues present the structure of the yeast 80S ribosome bound to 12 eukaryote-specific and 4 broad-spectrum inhibitors. On the basis of structural data and kinetic studies, the authors propose a model for the action of cycloheximide and lactimidomycin that demonstrates that the size of an inhibitor can dictate its accessibility to the ribosome and thus its mechanism of action. This new model suggests general principles for structure-based design of new antibiotics as well as therapeutics against fungal and protozoan infections, cancers and genetic disorders induced by premature stop codons.

Understanding translational control in gene expression relies on precise and comprehensive determination of translation initiation sites (TIS) across the entire transcriptome. The recently developed ribosome-profiling technique enables global translation analysis, providing a wealth of information about both the position and the density of ribosomes on mRNAs. Here we present an approach, global translation initiation sequencing, applying in parallel the ribosome E-site translation inhibitors lactimidomycin and cycloheximide to achieve simultaneous detection of both initiation and elongation events on a genome-wide scale. This approach provides a view of alternative translation initiation in mammalian cells with single-nucleotide resolution. Systemic analysis of TIS positions supports the ribosome linear-scanning mechanism in TIS selection. The alternative TIS positions and the associated ORFs identified by global translation initiation sequencing are conserved between human and mouse cells, implying physiological significance of alternative translation. Our study establishes a practical platform for uncovering the hidden coding potential of the transcriptome and offers a greater understanding of the complexity of translation initiation.

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

Curcumin has anti-tumour and antibacterial effects. In this research, fourteen kinds of piperidone monocarbonyl curcumin analogues with 3,5-dimethylene-4-piperidone as the parent scaffold and halogen substitution on both sides of the benzene ring were synthesized by Claisen–Schmidt reaction, and their anti-tumour effect, mechanism, and antibacterial activity were investigated. It was found that a series of curcumin analogues has different degrees of anti-tumour and antibacterial dual activity. Among them, 2,5-2Cl, 2Br-5Cl, 2-Cl, 2-F, and benzaldehyde have strong broad-spectrum anti-tumour effects and have obvious selective inhibitory effects on A549 cells. The IC50 value is less than 5 μmol/L. The five promising compounds, respectively, inhibited the expression of AKT and ERK to induce apoptosis of A549 cells to varying degrees. The newly synthesized analogues 2,5-2Cl and 2Br-5Cl had stronger inhibitory effects on the growth of A549 cells than other analogues, and they tended to mainly inhibit the expression of AKT and ERK, respectively. However, 2-Cl and 2-F have significantly better inhibitory effects on methicillin-resistant Staphylococcus aureus (MRSA) than antibiotics. Taken together, piperidone monocarbonyl curcumin analogues may be developed as good candidates for potential prevention and treatment of cancer and bacterial infection complications.

Background. Sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs whose anti-inflammatory properties have recently become useful in tackling metabolic syndromes in chronic inflammatory diseases, including diabetes and obesity. We investigated whether empagliflozin (SGLT2 inhibitor) and gemigliptin (DPP-4 inhibitor) improve inflammatory responses in macrophages, identified signalling pathways responsible for these effects, and studied whether the effects can be augmented with dual empagliflozin and gemigliptin therapy. Methods. RAW 264.7 macrophages were first stimulated with lipopolysaccharide (LPS), then cotreated with empagliflozin, gemigliptin, or empagliflozin plus gemigliptin. We conducted quantitative RT-PCR (qRT-PCR) to determine the most effective anti-inflammatory doses without cytotoxicity. We performed ELISA and qRT-PCR for inflammatory cytokines and chemokines and flow cytometry for CD80, the M1 macrophage surface marker, to evaluate the anti-inflammatory effects of empagliflozin and gemigliptin. NF-κB, MAPK, and JAK2/STAT signalling pathways were examined via Western blotting to elucidate the molecular mechanisms of anti-inflammation. Results. LPS-stimulated CD80+ M1 macrophages were suppressed by coincubation with empagliflozin, gemigliptin, and empagliflozin plus gemigliptin, respectively. Empagliflozin and gemigliptin (individually and combined) inhibited prostaglandin E2 (PGE2) release and COX-2, iNOS gene expression in LPS-stimulated RAW 264.7 macrophages. These three treatments also attenuated the secretion and mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, and proinflammatory chemokines, such as CCL3, CCL4, CCL5, and CXCL10. All of them blocked NF-κB, JNK, and STAT1/3 phosphorylation through IKKα/β, MKK4/7, and JAK2 signalling. Conclusions. Our study demonstrated the anti-inflammatory effects of empagliflozin and gemigliptin via IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 pathway downregulation in macrophages. In all cases, combined empagliflozin and gemigliptin treatment showed greater anti-inflammatory properties.