New activators of eIF2α Kinase Heme-Regulated Inhibitor (HRI) with improved biophysical properties

Zhang, Qingwen; Du, Ronghui; Santos, Guilherme Rodrigo Reis Monteiro dos; Yefidoff-Freedman, Revital; Bohm, Andrew; Halperin, José A.; Chorev, Michael; Aktas, Bertal H.

doi:10.1016/j.ejmech.2019.111973

Cited by 14 publications

(5 citation statements)

References 32 publications

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“…Identification, synthesis, structure–activity relationship studies, and biological evaluation of the compounds used for these studies are described in [ 17 , 18 , 22 , 23 , 24 ]. The compounds I-17 and 3m , whose synthesis was originally described in [ 18 ] and [ 22 ], were purified to >98% by flash chromatography and dried as a white powder.…”

Section: Methodsmentioning

confidence: 99%

Activity of the Di-Substituted Urea-Derived Compound I-17 in Leishmania In Vitro Infections

dos Santos,

Medina,

Dias Teixeira

et al. 2024

Pathogens

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Protein synthesis has been a very rich target for developing drugs to control prokaryotic and eukaryotic pathogens. Despite the development of new drug formulations, treating human cutaneous and visceral Leishmaniasis still needs significant improvements due to the considerable side effects and low adherence associated with the current treatment regimen. In this work, we show that the di-substituted urea-derived compounds I-17 and 3m are effective in inhibiting the promastigote growth of different Leishmania species and reducing the macrophage intracellular load of amastigotes of the Leishmania (L.) amazonensis and L. major species, in addition to exhibiting low macrophage cytotoxicity. We also show a potential immunomodulatory effect of I-17 and 3m in infected macrophages, which exhibited increased expression of inducible Nitric Oxide Synthase (NOS2) and production of Nitric Oxide (NO). Our data indicate that I-17, 3m, and their analogs may be helpful in developing new drugs for treating leishmaniasis.

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Section: Methodsmentioning

confidence: 99%

Activity of the Di-Substituted Urea-Derived Compound I-17 in Leishmania In Vitro Infections

dos Santos,

Medina,

Dias Teixeira

et al. 2024

Pathogens

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“…EIF2AK1, which is also recognized as heme-regulated inhibitor HRI (HRI), has a fundamental role in the translation of proteins that prevent the expression of HbF [118]. HRI is an erythrocyte kinase enzyme that inhibits the translation of HbF [119].…”

Section: Gt Approaches For Thalassemiamentioning

confidence: 99%

Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

Anurogo

Budi

Ngo

et al. 2021

IJMS

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Hereditary anemia has various manifestations, such as sickle cell disease (SCD), Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency (G6PDD), and thalassemia. The available management strategies for these disorders are still unsatisfactory and do not eliminate the main causes. As genetic aberrations are the main causes of all forms of hereditary anemia, the optimal approach involves repairing the defective gene, possibly through the transplantation of normal hematopoietic stem cells (HSCs) from a normal matching donor or through gene therapy approaches (either in vivo or ex vivo) to correct the patient’s HSCs. To clearly illustrate the importance of cell and gene therapy in hereditary anemia, this paper provides a review of the genetic aberration, epidemiology, clinical features, current management, and cell and gene therapy endeavors related to SCD, thalassemia, Fanconi anemia, and G6PDD. Moreover, we expound the future research direction of HSC derivation from induced pluripotent stem cells (iPSCs), strategies to edit HSCs, gene therapy risk mitigation, and their clinical perspectives. In conclusion, gene-corrected hematopoietic stem cell transplantation has promising outcomes for SCD, Fanconi anemia, and thalassemia, and it may overcome the limitation of the source of allogenic bone marrow transplantation.

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“…Numerous small molecules have been identified to activate these other ISR kinases. BtdCPU and related N,N’-diarylureas are activators of HRI signaling, although the mechanism by which these compounds activate HRI are poorly defined (Chen et al , 2011; Zhang et al , 2020). Alternatively, GCN2 is activated by the glutamyl- prolyl tRNA synthetase inhibitor halofuginone through a mechanism involving the accumulation of uncharged proline tRNA (Keller et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Perea

Baron

Dolina

et al. 2023

Preprint

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The integrated stress response (ISR) is a network of eIF2alpha 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. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk-deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.

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New activators of eIF2α Kinase Heme-Regulated Inhibitor (HRI) with improved biophysical properties

Cited by 14 publications

References 32 publications

Activity of the Di-Substituted Urea-Derived Compound I-17 in Leishmania In Vitro Infections

Activity of the Di-Substituted Urea-Derived Compound I-17 in Leishmania In Vitro Infections

Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

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