Selective targeting of the DEAD-box RNA helicase eukaryotic initiation factor (eIF) 4A by natural products

Shen, Leo; Pelletier, Jerry

doi:10.1039/c9np00052f

Cited by 40 publications

(38 citation statements)

References 53 publications

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“…The rocaglates target the translation initiation factor eIF4A in C. auris. Rocaglates have been reported to inhibit translation initiation in mammalian cells and S. cerevisiae through interaction with orthologues of the eukaryotic initiation factor 4A (eIF4A) (30)(31)(32)(33). In examining the rocaglates present in the BU-CMD collection, we found that all four hit rocaglates are among the strongest enhancers of human eIF4A1-polypurine RNA clamping (34), further supporting the identification of translation as a putative target.…”

Section: Resultsmentioning

confidence: 58%

Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris

Iyer

Whitesell

Porco

et al. 2020

mBio

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Fungal infections are a major contributor to infectious disease-related deaths worldwide. Recently, global emergence of the fungal pathogen Candida auris has caused considerable concern because most C. auris isolates are resistant to fluconazole, the most commonly administered antifungal, and some isolates are resistant to drugs from all three major antifungal classes. To identify novel agents with bioactivity against C. auris, we screened 2,454 compounds from a diversity-oriented synthesis collection. Of the five hits identified, most shared a common rocaglate core structure and displayed fungicidal activity against C. auris. These rocaglate hits inhibited translation in C. auris but not in its pathogenic relative Candida albicans. Species specificity was contingent on variation at a single amino acid residue in Tif1, a fungal member of the eukaryotic initiation factor 4A (eIF4A) family of translation initiation factors known to be targeted by rocaglates. Rocaglate-mediated inhibition of translation in C. auris activated a cell death program characterized by loss of mitochondrial membrane potential, increased caspase-like activity, and disrupted vacuolar homeostasis. In a rocaglate-sensitized C. albicans mutant engineered to express translation initiation factor 1 (Tif1) with the variant amino acid that we had identified in C. auris, translation was inhibited but no programmed cell death phenotypes were observed. This surprising finding suggests divergence between these related fungal pathogens in their pathways of cellular responses to translation inhibition. From a therapeutic perspective, the chemical biology that we have uncovered reveals species-specific vulnerability in C. auris and identifies a promising target for development of new, mechanistically distinct antifungals in the battle against this emerging pathogen. IMPORTANCE Emergence of the fungal pathogen Candida auris has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that C. auris is surprisingly sensitive to translation inhibition by a class of compounds known as rocaglates (also known as flavaglines). Despite the high level of conservation across fungi in their protein synthesis machinery, these compounds inhibited translation initiation and activated a cell death program in C. auris but not in its relative Candida albicans. Our findings highlight a surprising divergence across the cell death programs operating in Candida species and underscore the need to understand the specific biology of a pathogen in attempting to develop more-effective treatments against it.

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Section: Resultsmentioning

confidence: 58%

Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris

Iyer

Whitesell

Porco

et al. 2020

mBio

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“…There are three natural products that can be combined with EIF4A, including hippuristanol, pateamine A and rocaglates (41). Hippuristanol displays decreased effectiveness toward EIF4A3, requiring 10-fold higher concentrations compared with EIF4A1/2 (42).…”

Section: Eif4a3 Inhibitorsmentioning

confidence: 99%

Effect of eukaryotic translation initiation factor 4A3 in malignant tumors (Review)

Zhu

Ren

2021

Oncol Lett

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Eukaryotic translation initiation factor 4A3 (EIF4A3), a key component of the exon junction complex, is widely involved in RNA splicing and nonsense-mediated mRNA decay. EIF4A3 has also been reported to be involved in cell cycle regulation and apoptosis. Thus, EIF4A3 may serve as a pivotal regulatory factor involved in the occurrence and development of multiple diseases. Previous studies have demonstrated that EIF4A3 is mutated in neuromuscular degenerative lesions and is differentially expressed in several tumors, serving as a non-coding RNA binding protein to regulate its expression. In addition, studies have reported that inhibiting EIF4A3 can prevent tumor cell proliferation, thus, several researchers are trying to design and synthesize potent and selective EIF4A3 inhibitors. The present review summarizes the function of EIF4A3 in cell cycle and discusses it underlying molecular mechanisms that contribute to the occurrence of malignant diseases. In addition, EIF4A3 selective inhibitors, and bioinformatics analyses performed to analyze the expression and mutations of EIF4A3 in gynecological tumors and breast cancer, are also discussed.

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“…To date, several small molecules have been identified that selectively target DDX/DHX-box helicase family members, and these have been extensively reviewed in [163] (summarized in Table 2). In brief, helicase inhibitors can be stratified into two groups: (i) interfacial inhibitors, in which the compounds interact with both the protein target and the RNA, and (ii) compounds that inhibit RNA binding.…”

Section: Targeting Ddx/dhx-box Helicases In Translation Initiationmentioning

confidence: 99%

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen

Pelletier

2020

IJMS

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DExD (DDX)- and DExH (DHX)-box RNA helicases, named after their Asp-Glu-x-Asp/His motifs, are integral to almost all RNA metabolic processes in eukaryotic cells. They play myriad roles in processes ranging from transcription and mRNA-protein complex remodeling, to RNA decay and translation. This last facet, translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Studies aimed at better understanding this family of conserved proteins have revealed insights into their structures, catalytic mechanisms, and biological roles. They have also led to the development of chemical modulators that seek to exploit their essential roles in diseases. Herein, we review the most recent insights on several general and target-specific DDX/DHX helicases in eukaryotic translation initiation.

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Selective targeting of the DEAD-box RNA helicase eukaryotic initiation factor (eIF) 4A by natural products

Abstract: This highlight reviews natural products targeting of the eIF4A RNA helicase by interfering with RNA-binding or acting as interfacial inhibitors to increase RNA resident time.

Cited by 40 publications

References 53 publications

Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris

Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris

Effect of eukaryotic translation initiation factor 4A3 in malignant tumors (Review)

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

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