Striking gold: A series of variously functionalized propynyl arenes was smoothly converted into indan‐2‐ones by a new gold(I)‐catalyzed oxidative cyclization process. LAuNTf2 ...(Tf=trifluoromethanesulfonyl) is a superior catalyst both in terms of yield and kinetics for the present transformation.
Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy ...outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.
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Pulmonary melioidosis is a bacterial disease with high morbidity and a mortality rate that can be as high as 40% in resource-poor regions of South Asia. This disease burden is linked to the ...pathogen's intrinsic antibiotic resistance and protected intracellular localization in alveolar macrophages. Current treatment regimens require several antibiotics with multi-month oral and intravenous administrations that are difficult to implement in under-resourced settings. Herein, we report that a macrophage-targeted polyciprofloxacin prodrug acts as a surprisingly effective pre-exposure prophylactic in highly lethal murine models of aerosolized human pulmonary melioidosis. A single dose of the polymeric prodrug maintained high lung drug levels and targeted an intracellular depot of ciprofloxacin to the alveolar macrophage compartment that was sustained over a period of 7 days above minimal inhibitory concentrations. This intracellular pharmacokinetic profile provided complete pre-exposure protection in a BSL-3 model with an aerosolized clinical isolate of Burkholderia pseudomallei from Thailand. This total protection was achieved despite the bacteria's relative resistance to ciprofloxacin and where an equivalent dose of pulmonary-administered ciprofloxacin was ineffective. For the first time, we demonstrate that targeting the intracellular macrophage compartment with extended antibiotic dosing can achieve pre-exposure prophylaxis in a model of pulmonary melioidosis. This fully synthetic and modular therapeutic platform could be an important therapeutic approach with new or re-purposed antibiotics for melioidosis prevention and treatment, especially as portable inhalation devices in high-risk, resource-poor settings.
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The elucidation of protein/drug interactions remains a major challenge in drug discovery. Liquid chromatography–tandem mass spectrometry has emerged as a tremendously powerful technology for this ...endeavor, but its full potential has yet to be realized owing in part to unresolved challenges in data analysis. Herein, we demonstrate how tandem mass spectrometry can comprehensively map small molecule/peptide adducts when combined with unconstrained sequencing. Using a published sulfonyl fluoride activity-based probe as a model system, this method enabled the discovery of several unreported sites of interaction with its target proteins. Crucially, this probe was found to undergo quantitative displacement and hydrolysis from the target protein’s active site. Isotopic labeling experiments provided a mechanistic rationale for the observed hydrolysis that involves neighboring-group participation. A chemical biology tagging strategy that leverages the probe’s observed lability was developed and shown to be compatible with the original small molecule inhibitor in discovery profiling experiments.
Primaquine and tafenoquine are the two 8-aminoquinoline (8-AQ) antimalarial drugs approved for malarial radical cure - the elimination of liver stage hypnozoites after infection with Plasmodium ...vivax. A single oral dose of tafenoquine leads to high efficacy against intra-hepatocyte hypnozoites after efficient first pass liver uptake and metabolism. Unfortunately, both drugs cause hemolytic anemia in G6PD-deficient humans. This toxicity prevents their mass administration without G6PD testing given the approximately 400 million G6PD deficient people across malarial endemic regions of the world. We hypothesized that liver-targeted delivery of 8-AQ prodrugs could maximize liver exposure and minimize erythrocyte exposure to increase their therapeutic window. Primaquine and tafenoquine were first synthesized as prodrug vinyl monomers with self-immolative hydrolytic linkers or cathepsin-cleavable valine-citrulline peptide linkers. RAFT polymerization was exploited to copolymerize these prodrug monomers with hepatocyte-targeting GalNAc monomers. Pharmacokinetic studies of released drugs after intravenous administration showed that the liver-to-plasma AUC ratios could be significantly improved, compared to parent drug administered orally. Single doses of the liver-targeted, enzyme-cleavable tafenoquine polymer were found to be as efficacious as an equivalent dose of the oral parent drug in the P. berghei causal prophylaxis model. They also elicited significantly milder hemotoxicity in the humanized NOD/SCID mouse model engrafted with red blood cells from G6PD deficient donors. The clinical application is envisioned as a single subcutaneous administration, and the lead tafenoquine polymer also showed excellent bioavailability and liver-to-blood ratios exceeding the IV administered polymer. The liver-targeted tafenoquine polymers warrant further development as a single-dose therapeutic via the subcutaneous route with the potential for broader patient administration without a requirement for G6PD diagnosis.
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Approximately 3.3 billion people live with the threat of
malaria. Infection can result in liver-localized hypnozoites, which when reactivated cause relapsing malaria. This work demonstrates that an ...enzyme-cleavable polymeric prodrug of tafenoquine addresses key requirements for a mass administration, eradication campaign: excellent subcutaneous bioavailability, complete parasite control after a single dose, improved therapeutic window compared to the parent oral drug, and low cost of goods sold (COGS) at less than $1.50 per dose. Liver targeting and subcutaneous dosing resulted in improved liver:plasma exposure profiles, with increased efficacy and reduced glucose 6-phosphate dehydrogenase-dependent hemotoxicity in validated preclinical models. A COGS and manufacturability analysis demonstrated global scalability, affordability, and the ability to redesign this fully synthetic polymeric prodrug specifically to increase global equity and access. Together, this polymer prodrug platform is a candidate for evaluation in human patients and shows potential for
eradication campaigns.
Global projections of intense tropical cyclone activity are derived from the Geophysical Fluid Dynamics Laboratory (GFDL) High Resolution Atmospheric Model (HiRAM; 50-km grid) and the GFDL hurricane ...model using a two-stage downscaling procedure. First, tropical cyclone genesis is simulated globally using HiRAM. Each storm is then downscaled into the GFDL hurricane model, with horizontal grid spacing near the storm of 6 km, including ocean coupling (e.g., “cold wake” generation). Simulations are performed using observed sea surface temperatures (SSTs) (1980–2008) for a “control run” with 20 repeating seasonal cycles and for a late-twenty-first-century projection using an altered SST seasonal cycle obtained from a phase 5 of CMIP (CMIP5)/representative concentration pathway 4.5 (RCP4.5) multimodel ensemble. In general agreement with most previous studies, projections with this framework indicate fewer tropical cyclones globally in a warmer late-twenty-first-century climate, but also an increase in average cyclone intensity, precipitation rates, and the number and occurrence days of very intense category 4 and 5 storms. While these changes are apparent in the globally averaged tropical cyclone statistics, they are not necessarily present in each individual basin. The interbasin variation of changes in most of the tropical cyclone metrics examined is directly correlated to the variation in magnitude of SST increases between the basins. Finally, the framework is shown to be capable of reproducing both the observed global distribution of outer storm size—albeit with a slight high bias—and its interbasin variability. Projected median size is found to remain nearly constant globally, with increases in most basins offset by decreases in the northwest Pacific.
Erstaunliches Gold: Eine Serie funktionalisierter Propinylarene wurde durch einen neuen, milden Gold(I)‐katalysierten oxidativen Cyclisierungsprozess in Indan‐2‐one umgewandelt. LAuNTf2 ...(Tf=Trifluormethansulfonyl) erwies sich als der beste Katalysator bezüglich Ausbeute und Reaktionskinetik.
A major goal for X‐ray free‐electron laser (XFEL) based science is to elucidate structures of biological molecules without the need for crystals. Filament systems may provide some of the first single ...macromolecular structures elucidated by XFEL radiation, since they contain one‐dimensional translational symmetry and thereby occupy the diffraction intensity region between the extremes of crystals and single molecules. Here, we demonstrate flow alignment of as few as 100 filaments (Escherichia coli pili, F‐actin, and amyloid fibrils), which when intersected by femtosecond X‐ray pulses result in diffraction patterns similar to those obtained from classical fiber diffraction studies. We also determine that F‐actin can be flow‐aligned to a disorientation of approximately 5 degrees. Using this XFEL‐based technique, we determine that gelsolin amyloids are comprised of stacked β‐strands running perpendicular to the filament axis, and that a range of order from fibrillar to crystalline is discernable for individual α‐synuclein amyloids.
The paper considers an industry transforming primary commodities (farm products) into processed commodities (food products). It focuses on the allocation of embedded characteristics (carbohydrate, ...protein, etc.) both across space and among commodities. The approach generates a spatial competitive market equilibrium of production, consumption, transformation, and trade for both primary and processed commodities, along with the spatial distribution of shadow prices for the product characteristics. The model provides a basis for analyzing the allocation and pricing of agricultural products, food products, and characteristics in spatial markets. The empirical usefulness of the model is illustrated in the context of regional resource allocation in the U.S. dairy sector.
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