keyword
https://read.qxmd.com/read/34075378/single-molecule-dynamics-of-sars-cov-2-5-cap-recognition-by-human-eif4f
#21
Hea Jin Hong, Matthew G Guevara, Eric Lin, Seán E O'Leary
Coronaviruses initiate translation through recognition of the viral RNA 5' m 7 GpppA m cap by translation factor eIF4F. eIF4F is a heterotrimeric protein complex with cap-binding, RNA-binding, and RNA helicase activities. Modulating eIF4F function through cellular regulation or small-molecule inhibition impacts coronavirus replication, including for SARS-CoV-2. Translation initiation involves highly coordinated dynamics of translation factors with messenger or viral RNA. However, how the eIF4F subunits coordinate on the initiation timescale to define cap-binding efficiency remains incompletely understood...
May 27, 2021: bioRxiv
https://read.qxmd.com/read/34058326/natural-products-as-drugs-and-tools-for-influencing-core-processes-of-eukaryotic-mrna-translation
#22
REVIEW
Luisa D Burgers, Robert Fürst
Eukaryotic protein synthesis is the highly conserved, complex mechanism of translating genetic information into proteins. Although this process is essential for cellular homoeostasis, dysregulations are associated with cellular malfunctions and diseases including cancer and diabetes. In the challenging and ongoing search for adequate treatment possibilities, natural products represent excellent research tools and drug leads for new interactions with the translational machinery and for influencing mRNA translation...
August 2021: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://read.qxmd.com/read/33861954/a-double-on-the-rocs-with-a-twist-rocaglamide-a-targets-multiple-dead-box-helicases-to-inhibit-translation-initiation
#23
JOURNAL ARTICLE
Daisy J DiVita, Michael G Kearse
In this issue of Cell Chemical Biology, Chen et al. (2020) expand the target repertoire of rocaglamide A (RocA) to now include eIF4A2 and DDX3X, converting DEAD-box helicases into dominant-negative translation repressors. These results also highlight how cancer cell sensitivity to RocA is dependent on eIF4A and DDX3X levels.
April 15, 2021: Cell Chemical Biology
https://read.qxmd.com/read/33718171/mitophagy-in-pancreatic-cancer
#24
REVIEW
Yangchun Xie, Jiao Liu, Rui Kang, Daolin Tang
Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive solid malignancies, is characterized by the presence of oncogenic KRAS mutations, poor response to current therapies, prone to metastasis, and a low 5-year overall survival rate. Macroautophagy (herein referred to as autophagy) is a lysosome-dependent degradation system that forms a series of dynamic membrane structures to engulf, degrade, and recycle various cargoes, such as unused proteins, damaged organelles, and invading pathogens. Autophagy is usually upregulated in established cancers, but it plays a dual role in the regulation of the initiation and progression of PDAC...
2021: Frontiers in Oncology
https://read.qxmd.com/read/33705115/merging-strategy-improvisation-and-conversation-to-solve-problems-in-target-synthesis
#25
JOURNAL ARTICLE
Alison J Frontier, Paul P Sinclair
ConspectusTotal synthesis has long been depicted as the quest to conquer the structures created by nature, requiring an unflinching, single-minded devotion to the task. The goal is achieved by chemists with grit, strength of will, and a competitive spirit. While there is some truth to this viewpoint, it does not fully capture the rich experiences gained in this research realm. In our lab, strategic planning, improvisation, and conversation have worked in concert to enable progress. This Account summarizes our efforts to synthesize four different bioactive targets: merrilactone A, rocaglamide, phomactin A, and tetrapetalone A...
March 11, 2021: Accounts of Chemical Research
https://read.qxmd.com/read/33703953/chemical-constituents-of-aglaia-elaeagnoidea-and-aglaia-odorata-and-their-cytotoxicity
#26
JOURNAL ARTICLE
Ngoc T N Ngo, Ngan T D D T Lai, Hao C Le, Le-Thu T Nguyen, Binh T D Trinh, Hiep D Nguyen, Phuoc D Pham, Son V Dang, Lien-Hoa D Nguyen
Two new rocaglamides, 8b- O -5-oxohexylrocaglaol ( 1 ) and elaeagnin ( 2 ), together with twelve known compounds, were isolated from the bark of Aglaia elaeagnoidea and the whole tree of A. odorata . Their structures were determined using spectroscopic methods, mainly 1D and 2D NMR. Cytotoxic activity against HepG2 human liver cancer cells of the isolated compounds was evaluated in vitro using the SRB assay. Three rocaglamide derivatives, dehydroaglaiastatin ( 13 ), 8b- O -5-oxohexylrocaglaol ( 1 ) and rocaglaol ( 5 ), exhibited significant effects with IC50 values of 0...
March 11, 2021: Natural Product Research
https://read.qxmd.com/read/33412110/functional-mimicry-revealed-by-the-crystal-structure-of-an-eif4a-rna-complex-bound-to-the-interfacial-inhibitor-desmethyl-pateamine-a
#27
JOURNAL ARTICLE
Sai Kiran Naineni, Jason Liang, Kenneth Hull, Regina Cencic, Mingzhao Zhu, Peter Northcote, Paul Teesdale-Spittle, Daniel Romo, Bhushan Nagar, Jerry Pelletier
Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of an eIF4A1:RNA complex bound to an analog of the marine sponge-derived natural product PatA, C5-desmethyl PatA (DMPatA). One end of this small molecule wedges itself between two RNA bases while the other end is cradled by several protein residues...
January 5, 2021: Cell Chemical Biology
https://read.qxmd.com/read/33296667/dual-targeting-of-ddx3-and-eif4a-by-the-translation-inhibitor-rocaglamide-a
#28
JOURNAL ARTICLE
Mingming Chen, Miwako Asanuma, Mari Takahashi, Yuichi Shichino, Mari Mito, Koichi Fujiwara, Hironori Saito, Stephen N Floor, Nicholas T Ingolia, Mikiko Sodeoka, Kosuke Dodo, Takuhiro Ito, Shintaro Iwasaki
The translation inhibitor rocaglamide A (RocA) has shown promising antitumor activity because it uniquely clamps eukaryotic initiation factor (eIF) 4A onto polypurine RNA for selective translational repression. As eIF4A has been speculated to be a unique target of RocA, alternative targets have not been investigated. Here, we reveal that DDX3 is another molecular target of RocA. Proximity-specific fluorescence labeling of an O-nitrobenzoxadiazole-conjugated derivative revealed that RocA binds to DDX3. RocA clamps the DDX3 protein onto polypurine RNA in an ATP-independent manner...
December 2, 2020: Cell Chemical Biology
https://read.qxmd.com/read/33292639/protein-synthesis-inhibitors-stimulate-mondoa-transcriptional-activity-by-driving-an-accumulation-of-glucose-6-phosphate
#29
JOURNAL ARTICLE
Blake R Wilde, Mohan R Kaadige, Katrin P Guillen, Andrew Butterfield, Bryan E Welm, Donald E Ayer
BACKGROUND: Protein synthesis is regulated by the availability of amino acids, the engagement of growth factor signaling pathways, and adenosine triphosphate (ATP) levels sufficient to support translation. Crosstalk between these inputs is extensive, yet other regulatory mechanisms remain to be characterized. For example, the translation initiation inhibitor rocaglamide A (RocA) induces thioredoxin-interacting protein (TXNIP). TXNIP is a negative regulator of glucose uptake; thus, its induction by RocA links translation to the availability of glucose...
December 4, 2020: Cancer & Metabolism
https://read.qxmd.com/read/33201461/known-inhibitors-of-rna-helicases-and-their-therapeutic-potential
#30
JOURNAL ARTICLE
Yosser Zina Abdelkrim, Josette Banroques, N Kyle Tanner
RNA helicases are proteins found in all kingdoms of life, and they are associated with all processes involving RNA from transcription to decay. They use NTP binding and hydrolysis to unwind duplexes, to remodel RNA structures and protein-RNA complexes, and to facilitate the unidirectional metabolism of biological processes. Viral, bacterial, and eukaryotic parasites have an intimate need for RNA helicases in their reproduction. Moreover, various disorders, like cancers, are often associated with a perturbation of the host's helicase activity...
2021: Methods in Molecular Biology
https://read.qxmd.com/read/33130371/phytochemistry-and-biological-activities-of-aglaia-species
#31
REVIEW
Desi Harneti, Unang Supratman
Aglaia is the largest genus in the Meliaceae family (also known as Mahagoni in Indonesia), consisting of over 150 species, of which 65 are indigenous to Indonesia. These species spread through the tropical regions, especially Southeast Asia as well as the Nothern part of Australia, and have been used in traditional medicine for the treatment of several diseases. However, preliminary chemical researches commenced in 1965, where dammarane-type triterpenoids, aglaiol was isolated, and the structure was determined by chemical reaction and spectroscopic methods...
October 23, 2020: Phytochemistry
https://read.qxmd.com/read/32806219/strategic-diastereoselective-c1-functionalization-in-the-aza-rocaglamide-scaffold-toward-natural-product-inspired-eif4a-inhibitors
#32
JOURNAL ARTICLE
Christian Nilewski, Theodore D Michels, Alan X Xiang, Garrick K Packard, Paul A Sprengeler, Boreth Eam, Sarah Fish, Peggy A Thompson, Christopher J Wegerski, Justin T Ernst, Siegfried H Reich
Rocaglates, rocaglamides, and related flavagline natural products exert their remarkable anticancer activity through inhibition of eukaryotic initiation factor 4A (eIF4A) but generally display suboptimal drug-like properties. In our efforts to identify potent drug-like eIF4A inhibitors, we developed synthetic strategies for diastereoselectively functionalizing the C1 position of aza-rocaglamide scaffolds (cf. 14 and 18 ), which proceed via retention or inversion of configuration at C1 depending on the C2 substituent (cf...
July 30, 2020: Organic Letters
https://read.qxmd.com/read/32790284/new-twists-in-nazarov-cyclization-chemistry
#33
JOURNAL ARTICLE
Alison J Frontier, Jackson J Hernandez
ConspectusThe defining feature of the Nazarov cyclization is a 4π-conrotatory electrocyclization, resulting in the stereospecific formation of functionalized cyclopentanones. The reaction provides access to structural motifs that are found in many natural products and drug targets. Harnessing the full potential of the Nazarov cyclization broadens its utility by enabling the development of new methodologies and synthetic strategies. To achieve these goals through efficient cyclization design, it is helpful to think of the reaction as a two-stage process...
August 13, 2020: Accounts of Chemical Research
https://read.qxmd.com/read/32759815/identification-of-cardiac-glycosides-as-novel-inhibitors-of-eif4a1-mediated-translation-in-triple-negative-breast-cancer-cells
#34
JOURNAL ARTICLE
Cory M Howard, Matthew Estrada, David Terrero, Amit K Tiwari, Dayanidhi Raman
The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5'-leader region of a luciferase-tdTomato lentiviral reporter construct...
August 4, 2020: Cancers
https://read.qxmd.com/read/32699874/rocaglamide-and-silvestrol-a-long-story-from-anti-tumor-to-anti-coronavirus-compounds
#35
JOURNAL ARTICLE
Göran Schulz, Catherine Victoria, Andreas Kirschning, Eike Steinmann
Covering: up to the beginning of 2020Many natural substances have been transformed again and again with regard to their pharmaceutical-medical potential, including new members of a growing class of natural products, the flavaglines. Important representatives are rocaglamide and silvestrol, isolated from the Aglaia species, which are highlighted here. These products started as potential anti-tumor agents five decades ago and have recently proved to be very promising antiviral agents, especially against RNA viruses...
July 23, 2020: Natural Product Reports
https://read.qxmd.com/read/32501281/a-subset-of-flavaglines-inhibits-kras-nanoclustering-and-activation
#36
JOURNAL ARTICLE
Hajime Yurugi, Yinyin Zhuang, Farid A Siddiqui, Hong Liang, Sebastian Rosigkeit, Yongpeng Zeng, Hussein Abou-Hamdan, Ernesto Bockamp, Yong Zhou, Daniel Abankwa, Wenting Zhao, Laurent Désaubry, Krishnaraj Rajalingam
The RAS oncogenes are frequently mutated in human cancers and among the three isoforms ( KRAS , HRAS and NRAS ), KRAS is the most frequently mutated oncogene. Here, we demonstrate that a subset of flavaglines, a class of natural anti-tumour drugs and chemical ligands of prohibitins, inhibit RAS GTP loading and oncogene activation in cells at nanomolar concentrations. Treatment with rocaglamide, the first discovered flavagline, inhibited the nanoclustering of KRAS, but not HRAS and NRAS, at specific phospholipid-enriched plasma membrane domains...
June 24, 2020: Journal of Cell Science
https://read.qxmd.com/read/32470302/design-of-development-candidate-eft226-a-first-in-class-inhibitor-of-eukaryotic-initiation-factor-4a-rna-helicase
#37
JOURNAL ARTICLE
Justin T Ernst, Peggy A Thompson, Christian Nilewski, Paul A Sprengeler, Samuel Sperry, Garrick Packard, Theodore Michels, Alan Xiang, Chinh Tran, Christopher J Wegerski, Boreth Eam, Nathan P Young, Sarah Fish, Joan Chen, Haleigh Howard, Jocelyn Staunton, Jolene Molter, Jeff Clarine, Andres Nevarez, Gary G Chiang, Jim R Appleman, Kevin R Webster, Siegfried H Reich
Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products ( i.e. , rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity...
May 29, 2020: Journal of Medicinal Chemistry
https://read.qxmd.com/read/32360851/the-strong-inhibitory-effect-of-combining-anti-cancer-drugs-at406-and-rocaglamide-with-blue-led-irradiation-on-colorectal-cancer-cells
#38
JOURNAL ARTICLE
Congwen Li, Guodong Zhu, Zihong Cui, Jihong Zhang, Shengting Zhang, Yunlin Wei
There is still no satisfying method to treat colorectal cancer (CRC) currently. Inspired by cocktail therapy, the combination of 465 nm blue LED irradiation and two multi-target anticancer agents AT406 and Rocaglamide has been investigated for a revolutionary way to treat colorectal cancer cells in vitro. It showed a strong inhibitory effect on colorectal cancer cells, and its side effects on human normal cells are negligible. When applied to HCT116 cells, it can achieve an apoptotic rate up to 95%. It is also seen to significantly inhibit proliferation of HT29 cells...
April 29, 2020: Photodiagnosis and Photodynamic Therapy
https://read.qxmd.com/read/31867270/targeting-of-the-eukaryotic-translation-initiation-factor-4a-against-breast-cancer-stemness
#39
JOURNAL ARTICLE
Sangita Sridharan, Megan Robeson, Diwakar Bastihalli-Tukaramrao, Cory M Howard, Boopathi Subramaniyan, Augustus M C Tilley, Amit K Tiwari, Dayanidhi Raman
Breast cancer stem cells (BCSCs) are intrinsically chemoresistant and capable of self-renewal. Following chemotherapy, patients can develop minimal residual disease due to BCSCs which can repopulate into a relapsed tumor. Therefore, it is imperative to co-target BCSCs along with the bulk tumor cells to achieve therapeutic success and prevent recurrence. So, it is vital to identify actionable molecular targets against both BCSCs and bulk tumor cells. Previous findings from our lab and others have demonstrated that inhibition of the emerging drug target eIF4A with Rocaglamide A (RocA) was efficacious against triple-negative breast cancer cells (TNBC)...
2019: Frontiers in Oncology
https://read.qxmd.com/read/31848295/targeting-protein-translation-by-rocaglamide-and-didesmethylrocaglamide-to-treat-mpnst-and-other-sarcomas
#40
JOURNAL ARTICLE
Long-Sheng Chang, Janet L Oblinger, Sarah S Burns, Jie Huang, Lawrence W Anderson, Melinda G Hollingshead, Rulong Shen, Li Pan, Garima Agarwal, Yulin Ren, Ryan D Roberts, Barry R O'Keefe, A Douglas Kinghorn, Jerry M Collins
Malignant peripheral nerve sheath tumors (MPNSTs) frequently overexpress eIF4F components, and the eIF4A inhibitor silvestrol potently suppresses MPNST growth. However, silvestrol has suboptimal drug-like properties, including a bulky structure, poor oral bioavailability (<2%), sensitivity to MDR1 efflux, and pulmonary toxicity in dogs. We compared 10 silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable to silvestrol...
December 17, 2019: Molecular Cancer Therapeutics
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