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Feline infectious peritonitis (FIP) is a fatal disease of cats that currently lacks licensed and affordable vaccines or antiviral therapeutics. The disease has a spectrum of clinical presentations including an effusive (“wet”) form and non-effusive (“dry”) form, both of which may be complicated by neurologic or ocular involvement. The feline coronavirus (FCoV) biotype, termed feline infectious peritonitis virus (FIPV), is the etiologic agent of FIP. The objective of this study was to determine and compare the in vitro antiviral efficacies of the viral protease inhibitors GC376 and nirmatrelvir and the nucleoside analogs remdesivir (RDV), GS-441524, molnupiravir (MPV; EIDD-2801), and β-D-N4-hydroxycytidine (NHC; EIDD-1931). These antiviral agents were functionally evaluated using an optimized in vitro bioassay system. Antivirals were assessed as monotherapies against FIPV serotypes I and II and as combined anticoronaviral therapies (CACT) against FIPV serotype II, which provided evidence for synergy for selected combinations. We also determined the pharmacokinetic properties of MPV, GS-441524, and RDV after oral administration to cats in vivo as well as after intravenous administration of RDV. We established that orally administered MPV at 10 mg/kg, GS-441524 and RDV at 25 mg/kg, and intravenously administered RDV at 7 mg/kg achieves plasma levels greater than the established corresponding EC50 values, which are sustained over 24 h for GS-441514 and RDV.

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate these agents are potent inhibitors of N . fowleri ENO ( Nf ENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC 50 = 0.14 ± 0.04 μM) that was toxic to trophozoites (EC 50 = 0.21 ± 0.02 μM) while the reported CC 50 was >300 μM. Molecular docking simulation revealed that HEX binds strongly to the active site of Nf ENO with a binding affinity of –8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of Nf ENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the end of the one-week observation, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. However, intranasal HEX delivery was not curative as brains of six of the eight survivors were positive for amoebae. These findings suggest that HEX requires further evaluation to develop as a lead for treatment of PAM.

Background Boron neutron capture therapy relies on the selective accumulation of boron-containing compounds in tumor tissue, making accurate quantification of boron distribution essential for effective treatment planning. The amino acid analog boronophenylalanine is widely used as a boron delivery agent, yet direct assessment of its biodistribution remains challenging. A fluorine-18 labeled analog, 2-fluoro-boronophenylalanine, offers the potential to visualize and quantify uptake through positron emission tomography. However, reported radiosynthetic methods often suffer from low radiochemical yield, complex workflows, and limited compatibility with automated production platforms. The aim of this study was to design a stable precursor suitable for nucleophilic fluorination, develop a fully automated single-reactor radiosynthesis, and characterize the resulting tracer to support both preclinical use and future clinical translation. Results A rationally protected precursor incorporating tert-butyloxycarbonyl and pinacol ester groups was synthesized and isolated with high chemical and enantiomeric purity. Using this precursor, an automated single-pot radiosynthesis was implemented on a commercial synthesis module employing copper-mediated nucleophilic fluorination followed by acidic hydrolysis. Across eight production runs, the method yielded 2-fluoro-boronophenylalanine with non-decay-corrected radiochemical yields of 3–5% and a total synthesis time of approximately 60–70 min. Radiochemical purity consistently exceeded 98%, and the molar activity at the end of synthesis ranged from 85 to 120 GBq per micromole. The final formulation remained chemically and radiochemically stable for at least four hours at room temperature. Analytical and chiral chromatographic assessments confirmed product identity, purity, and retention of stereochemical configuration. Conclusions This study establishes a practical and fully automated radiosynthetic approach for producing 2-fluoro-boronophenylalanine using a single-reactor nucleophilic fluorination strategy. The method overcomes key limitations of electrophilic fluorination and multi-pot workflows, provides high radiochemical purity and suitable molar activity, and is compatible with commercially available synthesis equipment. These features support routine preclinical application and position the method for future current good manufacturing practice adaptation to enable clinical use in boron neutron capture therapy planning.

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1 -deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1 -deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings. Oncogenic transformation can render cancer cells dependent on aberrant expression of glycolytic enzyme isoforms. Lin et al. describe a novel enolase inhibitor, POMHEX, that can selectively kill ENO1 -deleted glioblastomas.

Background4-[18F]fluorobenzyl-triphenylphosphonium ([18F]FBnTP) is a lipophilic cation PET tracer. The cellular uptake of [18F]FBnTP is correlated with oxidative phosphorylation by mitochondria, which has been associated with multiple critical diseases. To date, [18F]FBnTP has been successfully applied for imaging myocardial perfusion, assessment of severity of coronary artery stenosis, delineation of the ischemic area after transient coronary occlusion, and detection/quantification of apoptosis in various animal models. Recent preclinical and clinical studies have also expanded the possibilities of using [18F]FBnTP in oncological diagnosis and therapeutic monitoring. However, [18F]FBnTP is typically prepared through a tediously lengthy four-step, three-pot reaction and required multiple synthesizer modules; Thus, such an approach remains a challenge for this promising radiopharmaceutical to be implemented for routine clinical studies. Herein, we report an optimized one-step, one-pot automated approach to produce [18F]FBnTP through a single standard commercially-available radiosynthesizer that enables centralized production for clinical use.ResultsThe fully automated production of [18F]FBnTP took less than 55 min with radiochemical yields ranging from 28.33 ± 13.92% (non-decay corrected), apparent molar activity of 69.23 ± 45.62 GBq/µmol, and radiochemical purities of 99.79 ± 0.41%. The formulated [18F]FBnTP solution was determined to be sterile and colorless with a pH of 4.0–6.0. Our data has indicated no observable radiolysis after 8 h from the time of final product formulation and maximum assay of 7.88 GBq.ConclusionsA simplified and cGMP-compliant radiosynthesis of [18F]FBnTP has been established on the commercially available synthesizer in high activity concentration and radiochemical purity. While the preclinical and clinical studies using [18F]FBnTP PET are currently underway, the automated approaches reported herein facilitate clinical adoption of this radiotracer and warrant centralized production of [18F]FBnTP for imaging multiple patients.

A plethora of present studies has the purpose of analyzing the connection related to the effect of environmental, social, and governance (ESG) on business performance. However, it has still not been able to bring out comprehensive results because of using a single metric to measure performance. Due to that, this research will: (i) use the data envelopment analysis (DEA) method to measure transportation firms’ performance and (ii) use OLS regression to explore the relationship between ESG combined score and business performance. In the first stage, we found out that 43 out of 56 firms work inefficiently. The managers of those companies should utilize their resources and refer to the benchmarking as a sample to follow. The environmental and social scores positively affect business performance in the second stage. Thus, managers should consider ESG as an investment, primarily when transportation is categorized as an “environmentally sensitive industry”. Besides, investors should pay more attention to a company that has ESG activities because that firm has the chance to improve its business performance and deal with its commitments.

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) was a potent enzyme inhibitor (IC50 value of 0.60 ± 0.23 µM), while a six-membered ring-bearing phosphonate, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX), was less potent (IC50 value of 2.1 ± 1.1 µM). An analog with a larger seven-membered ring, (1-hydroxy-2-oxoazepan-3-yl) phosphonic acid (HEPTA), was not active. Molecular docking simulations revealed that deoxy-SF2312 and HEX had binding affinities of −6.8 and −7.5 kcal/mol, respectively, while the larger HEPTA did not bind as well, with a binding of affinity of −4.8 kcal/mol. None of these compounds were toxic to BSF parasites; however, modification of enzyme-active phosphonates through the addition of pivaloyloxymethyl (POM) groups improved activity against T. brucei, with POM-modified (1,5-dihydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (POMSF) and POMHEX having EC50 values of 0.45 ± 0.10 and 0.61 ± 0.08 µM, respectively. These findings suggest that HEX is a promising lead against T. brucei and that further development of prodrug HEX analogs is warranted.

In the original publication [...]

Background Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently described a novel enolase inhibitor, HEX, and its pro-drug POMHEX. Since glycolysis inhibition would deprive the cell of a key source of pyruvate, we hypothesized that enolase inhibitors might inhibit anaplerosis and synergize with other inhibitors of anaplerosis, such as the glutaminase inhibitor, CB-839. Methods We analyzed polar metabolites in sensitive ( ENO1 -deleted) and resistant ( ENO1 -WT) glioma cells treated with enolase and glutaminase inhibitors. We investigated whether sensitivity to enolase inhibitors could be attenuated by exogenous anaplerotic metabolites. We also determined the synergy between enolase inhibitors and the glutaminase inhibitor CB-839 in glioma cells in vitro and in vivo in both intracranial and subcutaneous tumor models. Results Metabolomic profiling of ENO1 -deleted glioma cells treated with the enolase inhibitor revealed a profound decrease in the TCA cycle metabolites with the toxicity reversible upon exogenous supplementation of supraphysiological levels of anaplerotic substrates, including pyruvate. ENO1- deleted cells also exhibited selective sensitivity to the glutaminase inhibitor CB-839, in a manner rescuable by supplementation of anaplerotic substrates or plasma-like media Plasmax TM . In vitro, the interaction of these two drugs yielded a strong synergistic interaction but the antineoplastic effects of CB-839 as a single agent in ENO1 -deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood-brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors. Conclusion Together, these data suggest that at least for ENO1 -deleted gliomas, tumors in vivo—unlike cells in culture—show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.

Boron neutron capture therapy relies on the selective accumulation of boron-containing compounds in tumor tissue, making accurate quantification of boron distribution essential for effective treatment planning. The amino acid analog boronophenylalanine is widely used as a boron delivery agent, yet direct assessment of its biodistribution remains challenging. A fluorine-18 labeled analog, 2-fluoro-boronophenylalanine, offers the potential to visualize and quantify uptake through positron emission tomography. However, reported radiosynthetic methods often suffer from low radiochemical yield, complex workflows, and limited compatibility with automated production platforms. The aim of this study was to design a stable precursor suitable for nucleophilic fluorination, develop a fully automated single-reactor radiosynthesis, and characterize the resulting tracer to support both preclinical use and future clinical translation.BACKGROUNDBoron neutron capture therapy relies on the selective accumulation of boron-containing compounds in tumor tissue, making accurate quantification of boron distribution essential for effective treatment planning. The amino acid analog boronophenylalanine is widely used as a boron delivery agent, yet direct assessment of its biodistribution remains challenging. A fluorine-18 labeled analog, 2-fluoro-boronophenylalanine, offers the potential to visualize and quantify uptake through positron emission tomography. However, reported radiosynthetic methods often suffer from low radiochemical yield, complex workflows, and limited compatibility with automated production platforms. The aim of this study was to design a stable precursor suitable for nucleophilic fluorination, develop a fully automated single-reactor radiosynthesis, and characterize the resulting tracer to support both preclinical use and future clinical translation.A rationally protected precursor incorporating tert-butyloxycarbonyl and pinacol ester groups was synthesized and isolated with high chemical and enantiomeric purity. Using this precursor, an automated single-pot radiosynthesis was implemented on a commercial synthesis module employing copper-mediated nucleophilic fluorination followed by acidic hydrolysis. Across eight production runs, the method yielded 2-fluoro-boronophenylalanine with non-decay-corrected radiochemical yields of 3-5% and a total synthesis time of approximately 60-70 min. Radiochemical purity consistently exceeded 98%, and the molar activity at the end of synthesis ranged from 85 to 120 GBq per micromole. The final formulation remained chemically and radiochemically stable for at least four hours at room temperature. Analytical and chiral chromatographic assessments confirmed product identity, purity, and retention of stereochemical configuration.RESULTSA rationally protected precursor incorporating tert-butyloxycarbonyl and pinacol ester groups was synthesized and isolated with high chemical and enantiomeric purity. Using this precursor, an automated single-pot radiosynthesis was implemented on a commercial synthesis module employing copper-mediated nucleophilic fluorination followed by acidic hydrolysis. Across eight production runs, the method yielded 2-fluoro-boronophenylalanine with non-decay-corrected radiochemical yields of 3-5% and a total synthesis time of approximately 60-70 min. Radiochemical purity consistently exceeded 98%, and the molar activity at the end of synthesis ranged from 85 to 120 GBq per micromole. The final formulation remained chemically and radiochemically stable for at least four hours at room temperature. Analytical and chiral chromatographic assessments confirmed product identity, purity, and retention of stereochemical configuration.This study establishes a practical and fully automated radiosynthetic approach for producing 2-fluoro-boronophenylalanine using a single-reactor nucleophilic fluorination strategy. The method overcomes key limitations of electrophilic fluorination and multi-pot workflows, provides high radiochemical purity and suitable molar activity, and is compatible with commercially available synthesis equipment. These features support routine preclinical application and position the method for future current good manufacturing practice adaptation to enable clinical use in boron neutron capture therapy planning.CONCLUSIONSThis study establishes a practical and fully automated radiosynthetic approach for producing 2-fluoro-boronophenylalanine using a single-reactor nucleophilic fluorination strategy. The method overcomes key limitations of electrophilic fluorination and multi-pot workflows, provides high radiochemical purity and suitable molar activity, and is compatible with commercially available synthesis equipment. These features support routine preclinical application and position the method for future current good manufacturing practice adaptation to enable clinical use in boron neutron capture therapy planning.