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ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo–electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate–hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.

The ATP-binding cassette subfamily B member 1 (ABCB1) multidrug transporter P-glycoprotein plays a central role in clearance of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. We used double electron electron resonance spectroscopy to uncover the basis of stimulation of P-glycoprotein adenosine 5′-triphosphate (ATP) hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect its transport function. Our results reveal that substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites. By contrast, this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites. Together with previous data, our findings lead to a general model of substrate and inhibitor coupling to P-glycoprotein.

Asenapine maleate (ASPM) is a second-generation atypical antipsychotic that is approved for treating acute schizophrenia and bipolar disorder in adults by the US FDA. The major downside of ASPM therapy is rapid, extensive first-pass hepatic metabolism following its oral administration with a very low oral bioavailability of < 2%. In this work, we developed ASPM nanoformulations conjugated with ligands such as arginine-glycine-aspartic acid (RGD) and peptide dendrimers (PDs) with the intention of improving the oral bioavailability of the drug by targeting it to the intestinal lymphatic system (ILS). Peptide dendrimers (PDs), both lipidated and nonlipidated, were synthesized by Fmoc solid phase peptide synthesis (SPPS). Reverse phase high performance chromatography (RP-HPLC) was used to purify the synthesized PDs, and the PDs were characterized by differential scanning calorimetry (DSC) electrospray ionization mass spectroscopy (ESI + -MS), Nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy. The thin film hydration method was used to prepare liposomes, and the process variables affecting the liposome parameters were optimized using the Box‒Behnken design (BBD).Liposomes were PEGylated using DSPE-PEG-COOH 2000 and further conjugated with ligands (RGD, PD-1 and PD-2) using EDC-NHS chemistry. The formulation was characterized using different spectroscopic techniques. In vitro, cell line studies, such as cytotoxicity, cell uptake, uptake mechanism, and receptor saturation studies, were performed on both Caco2 and Raji-B cells. The pharmacokinetic parameters of the developed liposomal formulation were evaluated using pharmacokinetic studies on Sprague- Dawley (SD) rats. The psychostimulant-induced hyperactivity model was used to evaluate the pharmacodynamic performance of the developed formulations by measuring the reversal of hyperlocomotor activity induced by levodopa-carbidopa.

The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes.

Understanding how simple molecules are pieced together in organisms may aid biotechnological manipulation and synthetic approaches to complex natural products. The mantis-associated fungus Daldinia eschscholzii IFB-TL01 produces the unusually structured immunosuppressants (±)-dalesconols A and B, along with their congener (±)-dalesconol C, with the (−)-enantiomers in excess. Here we report that these structural and stereochemical peculiarities of dalesconols A–C are a result of promiscuous and atropselective couplings of radicals derived from 1,3,6,8-tetrahydroxynaphthalene, 1,3,8-trihydroxynaphthalene and 1,8-dihydroxynaphthalene. The observed (−)-enantiomeric excess is found to depend on the dominance of particular conformers of naphthol dimer intermediates, which are ligands of laccase. The dalesconol natural products are biosynthesised in an enantiomeric excess of 67%, rather than as a single enantiomer or a racemate. Tan et al . report that this unusual enantioselectivity is a result of the dominance of particular conformers of naphthol dimer intermediates.

This case report stresses the importance of exercising caution when translating the names of prescribed drugs, especially when treating patients from abroad. We describe a young female migrant from Ukraine seeking help in the Danish mental healthcare system due to worsening psychotic symptoms. The misinterpretation of the sound-alike drugs Azapin (clozapine) and asenapine caused an acute dystonic reaction. This case illustrates various pitfalls regarding medication error. First, it uncovers a medication error due to a sound-alike drug and emphasises the importance of paying attention to national guidelines since first-line treatment can differ between countries. These factors combined increase the risk of medication error with potentially fatal consequences.

Purpose To determine if concomitant administration of docetaxel plus zosuquidar.3HC1 can prolong progression-free survival in patients with metastatic breast cancer. Methods A randomized, double-blind, multicenter, placebo-controlled clinical trial comparing docetaxel plus 500 mg zosuquidar.3HCl (DZ) with docetaxel plus placebo (DP). Results A total of 170 patients were enrolled and randomly assigned to treatment. The median age was 53 years (range, 31-74 years). 81.7% of patients had prior chemotherapy in the adjuvant setting and 18.3% in the neoadjuvant setting. The median progression-free survival time was statistically different between groups [7.2 months (DZ) vs. 8.3 months (DP)]. Once the stratification factor relative to progression following prior chemotherapy was considered, no significant treatment difference existed. Conclusion The combination of zosuquidar.3HCl plus docetaxel is safe. The analysis of efficacy data is complex, but it can be concluded that there is no difference in progression-free survival, overall survival, or response rate in the study as a whole.

The emergence of antibiotic resistance continues to pose a significant global challenge. Drug repurposing, wherein existing therapeutics are evaluated for new applications, offers a promising strategy to address this issue. Farnesyltransferase inhibitors (FTIs), initially developed for cancer therapy, have demonstrated antimicrobial activity against several gram-positive bacteria. This study investigates their activity in combination with colistin against gram-positive and gram-negative bacteria. We focus on key ESKAPE ( E nterococcus faecium , S taphylococcus aureus , K lebsiella pneumoniae , A cinetobacter baumannii , P seudomonas aeruginosa , and E nterobacter species) pathogens while incorporating additional bacterial strains to provide a comprehensive understanding of differential responses and potential dose-dependent synergistic effects. Antimicrobial susceptibility was assessed using broth microdilution, while synergy was evaluated through checkerboard, time-kill, and growth kinetics assays. When combined with sub-inhibitory colistin, FTIs inhibited gram-negative bacterial growth. Tipifarnib exhibited more potent antimicrobial activity against gram-negative strains than lonafarnib. Peptidomimetic FTIs, B581 and FTI-277, inhibited gram-negative bacteria in combination with colistin but had no effect on the gram-positive strains tested. In contrast, alpha-hydroxy farnesyl phosphonic acid, an FPP analog, and bempedoic acid, targeting the mevalonate pathway, showed no antibacterial activity. In addition to their known inhibition of gram-positive bacteria, FTIs exhibited efficacy against gram-negative bacteria, including colistin-resistant Enterobacter cloacae subsp. cloacae , when combined with sub-inhibitory colistin. This might be due to a mechanism distinct from their eukaryotic targets, potentially involving the disruption of multiple biosynthetic pathways. Future studies will focus on elucidating these mechanisms of FTIs and exploring the therapeutic potential of FTI/colistin combinations against ESKAPE and other multidrug-resistant pathogens.

The role of the inflammasomes in aging and progeroid syndromes remain understud-ied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24−/− mice to amelio-rate the phenotypes. However, the safety of MCC950 was questioned due to livertoxicity observed in humans. Nevertheless, inhibition of the inflammasomes wouldbe a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile),other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fi-broblasts and a Lmna G609G/G609G mouse model. In both cases dapansutrile reducedprogerin accumulation, NLRP3-inflammasome activation and secretory phenotype ofsenescence, extended the lifespan of progeroid animals, preserved bodyweight, andreduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile furtherimproved the effect of lonafarnib, the only FDA-approved drug for the progeria. Thecombination of both drugs reduced the inflammation and senescence, extended sur-vival and ameliorated various progeroid defects both in vitro and in vivo, comparedwith treatment using lonafarnib alone. These findings and the safety of dapansutriledemonstrated in several clinical trials proposes it as a possible co-adjuvant treatmentwith lonafarnid in HGPS

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.