halofuginone

Following a request from the European Commission, EFSA was asked to deliver a new scientific opinion on the coccidiostat halofuginone hydrobromide (STENOROL®) when used as a feed additive for chickens for fattening and turkeys for fattening/reared for breeding. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concludes that the safety for turkeys for fattening established in its previous opinion can be extended to turkeys for breeding up to 12 weeks of age. Based on the new data provided on the safety for consumer, environment and efficacy, the Panel updates its previous conclusions as follows: halofuginone hydrobromide is not genotoxic...

The antiparasitic drug halofuginone is important for controlling apicomplexan parasites. However, the occurrence of halofuginone resistance is a major obstacle for it to the treatment of apicomplexan parasites. Current studies have identified the molecular marker and drug resistance mechanisms of halofuginone in Plasmodium falciparum . In this study, we tried to use transcriptomic data to explore resistance mechanisms of halofuginone in apicomplexan parasites of the genus Eimeria (Apicomplexa: Eimeriidae). After halofuginone treatment of E...

Toxoplasma gondii (T. gondii) is one of the most successful parasites in the world, because about a third of the world's population is seropositive for toxoplasmosis. Treatment regimens for toxoplasmosis have remained unchanged for the past 20 years, and no new drugs have been introduced to the market recently. This study, performed molecular docking to identify interactions of FDA-approved drugs with essential residues in the active site of proteins of T. gondii Dihydrofolate Reductase (TgDHFR), Prolyl-tRNA Synthetase (TgPRS), and Calcium-Dependent Protein Kinase 1 (TgCDPK1)...

The control of coccidiosis, causing huge economic losses in the poultry industry, is facing the stagnation of the development of new drugs and the emergence of drug resistance. Thus, the priority for coccidiosis control is to decipher the effect mechanisms and resistance mechanisms of anticoccidial drugs. In this study, we mined and validated a molecular marker for halofuginone resistance in Eimeria tenella through forward and reverse genetic approaches. We screened whole-genome sequencing data and detected point mutations in the ETH2_1020900 gene (encoding prolyl-tRNA synthetase, PRS)...

The integrated stress response (ISR) is a network of eIF2 α kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK...

The prolyl-tRNA synthetase (PRS) is a validated drug target for febrifugine and its synthetic analog halofuginone (HFG) against multiple apicomplexan parasites including Plasmodium falciparum and Toxoplasma gondii. Here, a novel ATP-mimetic centered on 1-(pyridin-4-yl) pyrrolidin-2-one (PPL) scaffold has been validated to bind to Toxoplasma gondii PRS and kill toxoplasma parasites. PPL series exhibited potent inhibition at the cellular (T. gondii parasites) and enzymatic (TgPRS) levels compared to the human counterparts...

Nicotinamide N-methyltransferase (NNMT) has been reported to be linked to methylation reprogramming in cancer cells. However, the role of NNMT in the tumour microenvironment (TME) remains elusive. Here, we found that the expression of NNMT was elevated in the stroma of oral squamous cell carcinoma (OSCC). Using a fibroblast-attached organoids (FAOs) model, we confirmed that stromal NNMT expression contributed to the generation of assembled tumour organoids. In a tumour regeneration assay with co-implanted OSCC cells and cancer-associated fibroblasts (CAFs), the tumour-initiating activity was reduced when NNMT was silenced in CAFs...

Coccidiosis is a worldwide epidemic intestinal disease with high incidence, which causes huge economic losses. Halofuginone hydrobromide (HF) is widely applied as an effective anticoccidial drug in the poultry industry. However, its therapeutic efficacy is severely restrained due to toxic effects, poor aqueous solubility and low permeability. Nanotechnology can improve the biological effect of drugs, and thus, reduce administered doses and toxic effects. The objective of this study was to investigate the therapeutic and preventive potential of novel HF-loaded D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) polymer micelles (HTPM) for preventing coccidiosis in chickens...

Activating transcription factor 4 (ATF4) is involved in muscle atrophy through the overexpression of some atrogenes. However, it also controls the transcription of genes involved in muscle homeostasis maintenance. Here, we explored the effect of ATF4 activation by the pharmacological molecule halofuginone during hindlimb suspension (HS)-induced muscle atrophy. Firstly, we reported that periodic activation of ATF4-regulated atrogenes ( Gadd45a , Cdkn1a , and Eif4ebp1 ) by halofuginone was not associated with muscle atrophy in healthy mice...

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety for the target species of the coccidiostat halofuginone hydrobromide from STENOROL® when used as a feed additive for chickens for fattening and turkeys. In its previous assessment, the FEEDAP Panel could not conclude on the safety of STENOROL® for the target species at the highest proposed use level of 3 mg halofuginone hydrobromide/kg complete feed. On the basis of the new data provided, the FEEDAP Panel updates its previous conclusions on the safety for the target species as follows: halofuginone hydrobromide from STENOROL® is safe for chickens for fattening and for turkeys up to a maximum of 12 weeks of age at the highest proposed concentration of 3 mg/kg complete feed...

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial regions, with a high rate of metastasis. Cancer-associated fibroblasts (CAFs) play critical roles in tumor growth, metastasis and invasion, making them attractive therapeutic targets for cancer treatment. As an old anti-coccidiosis drug for poultry, Halofuginone (HF) has also been reported to possess anti-fibrosis and anti-cancer activities in the recent decades. However, whether it works by targeting CAFs in OSCC, and the mechanisms involved remain unclear...

Systemic lupus erythematosus (SLE) is a multisystemic, inflammatory autoimmune disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells participated in the pathogenesis of SLE. MDSCs has been considered a potential therapeutic target for lupus. As traditional Chinese medicine, Halofuginone (HF) has the extensive immunomodulatory effects on some autoimmune disorders. Our research was dedicated to discovering therapeutic efficacy of HF for lupus to explore novel mechanisms on MDSCs...

Aminoacyl-tRNA synthetases (aaRSs) are promising antimicrobial targets due to their essential roles in protein translation, and expanding their inhibitory mechanisms will provide new opportunities for drug discovery. We report here that halofuginone (HF), an herb-derived medicine, moderately inhibits prolyl-tRNA synthetases (ProRSs) from various pathogenic bacteria. A cocrystal structure of Staphylococcus aureus ProRS ( Sa ProRS) with HF and an ATP analog was determined, which guided the design of new HF analogs...

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of the product EnzaPro containing viable cells/spores of strains of Bacillus velezensis (DSM 21836) and Bacillus licheniformis (ATCC 53757) and an endo-1,4-β-xylanase produced by a genetically modified strain of Komagataella phaffii (DSM 33574) as a zootechnical additive in chickens for fattening, chickens reared for laying/breeding, turkeys for fattening, turkeys reared for breeding and minor poultry species for fattening or raised to the point of lay...

The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy. This was achieved by coassembling methoxy poly(ethylene glycol)- b -poly(caprolactone) with ketal-linked HF- and PTX-derived prodrugs...

The efficacy of radiotherapy is greatly challenged by intense hypoxia, intricate stroma and suppressive immune microenvironments in tumors. Herein, we rationally designed a microvesicle-inspired oxygen-delivering polyfluorocarbon nanosystem loading DiIC18(5) and halofuginone (M-FDH) with prominent capacity of improving tumor oxygenation and intratumor distribution, synergizing radiation to disrupt tumor stroma and boost antitumor immunity for combinational cancer therapy. M-FDH produced a 10.98-fold enhancement of tumor oxygenation and caused efficient production of reactive oxygen species (ROS) upon radiation...

Febrifugine, a natural alkaloid, exhibits specific anti-phytophthora activity; however, its mode of action is unclear. In this study, halofuginone, a synthetic derivative of febrifugine, showed significantly higher anti-phytophthora activities than those of febrifugine and the commercial drug metalaxyl against Phytophthora sojae , Phytophthora capsici , and Phytophthora infestans with effective concentration for 50% inhibition (EC50 ) values of 0.665, 0.673, and 0.178 μg/mL, respectively. Proline could alleviate the growth inhibition of halofuginone on P...

The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility...

The present study aimed to explore the effects of antifibrotic agent halofuginone on uterine leiomyomas (ULs) cells. The survival of the uterine smooth muscle (UtSMC) cells and UL ELT3 cells were measured. Flow cytometry was used to assess the cell cycle distribution and apoptosis. Effects of halofuginone on the state of AKT/mTOR pathway were evaluated. Xenograft animal model was applied to explore the effects of halofuginone in vivo . Halofuginone inhibited the proliferation of ELT3 cells dose-dependently without obvious influence on UtSMC cells...

TriTryp diseases (Leishmaniasis, Human African Trypanosomiasis (HAT), and Chagas disease) are devastating parasitic neglected tropical diseases (NTDs) that affect billions of people in developing countries, cause high mortality in humans, and impose a large socio-economic burden. The current treatment options against tritryp diseases are suboptimal and challenging due to the emergence of resistance against available tritryp drugs. Hence, designing and developing effective anti-tritryp drugs with novel targets are required...