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1.
Cell Rep ; 37(2): 109806, 2021 10 12.
Article in English | MEDLINE | ID: mdl-34644561

ABSTRACT

Tactical disruption of protein synthesis is an attractive therapeutic strategy, with the first-in-class eIF4A-targeting compound zotatifin in clinical evaluation for cancer and COVID-19. The full cellular impact and mechanisms of these potent molecules are undefined at a proteomic level. Here, we report mass spectrometry analysis of translational reprogramming by rocaglates, cap-dependent initiation disruptors that include zotatifin. We find effects to be far more complex than simple "translational inhibition" as currently defined. Translatome analysis by TMT-pSILAC (tandem mass tag-pulse stable isotope labeling with amino acids in cell culture mass spectrometry) reveals myriad upregulated proteins that drive hitherto unrecognized cytotoxic mechanisms, including GEF-H1-mediated anti-survival RHOA/JNK activation. Surprisingly, these responses are not replicated by eIF4A silencing, indicating a broader translational adaptation than currently understood. Translation machinery analysis by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) identifies rocaglate-specific dependence on specific translation factors including eEF1ε1 that drive translatome remodeling. Our proteome-level interrogation reveals that the complete cellular response to these historical "translation inhibitors" is mediated by comprehensive translational landscape remodeling.


Subject(s)
Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Animals , Benzofurans/pharmacology , Cell Line, Tumor , Eukaryotic Initiation Factor-4A/drug effects , Eukaryotic Initiation Factor-4A/metabolism , Humans , Male , Mice , Mice, Inbred NOD , Primary Cell Culture , Protein Biosynthesis/physiology , Proteomics/methods , Ribosomes/metabolism , Transcriptome/drug effects , Transcriptome/genetics , Triterpenes/pharmacology
2.
Eur J Med Chem ; 203: 112653, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-32693294

ABSTRACT

Flavaglines are cyclopenta[b]benzofurans found in plants of the genus Aglaia, several species of which are used in traditional Chinese medicine. These compounds target the initiation factor of translation eIF4A and the scaffold proteins prohibitins-1 and 2 (PHB1/2) to exert various pharmacological activities, including antiviral effects against several types of viruses, including coronaviruses. This review is focused on the antiviral effects of flavaglines and their therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Subject(s)
Aglaia/chemistry , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , Coronavirus Infections/drug therapy , Eukaryotic Initiation Factor-4A/genetics , Pneumonia, Viral/drug therapy , Repressor Proteins/genetics , Animals , COVID-19 , Eukaryotic Initiation Factor-4A/drug effects , Humans , Medicine, Chinese Traditional , Pandemics , Prohibitins , Repressor Proteins/drug effects
3.
Future Med Chem ; 5(18): 2185-97, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24261894

ABSTRACT

Flavaglines are complex natural products that are found in several medicinal plants of Southeast Asia in the genus Aglaia; these compounds have shown exceptional anticancer and cytoprotective activities. This review describes the significance of flavaglines as a new class of pharmacological agents and presents recent developments in their synthesis, structure-activity relationships, identification of their molecular targets and modes of action. Flavaglines display a unique profile of anticancer activities that are mediated by two classes of unrelated proteins: prohibitins and the translation initiation factor eIF4A. The identification of these molecular targets is expected to accelerate advancement toward clinical studies. The selectivity of cytotoxicity towards cancer cells has been shown to be due to an inhibition of the transcription factor HSF1 and an upregulation of the tumor suppressor TXNIP. In addition, flavaglines display potent anti-inflammatory, cardioprotective and neuroprotective activities; however, the mechanisms underlying these activities are yet to be elucidated.


Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Eukaryotic Initiation Factor-4A/drug effects , Repressor Proteins/antagonists & inhibitors , Antineoplastic Agents/chemistry , Biological Products/chemistry , Humans , Prohibitins , Structure-Activity Relationship
4.
ACS Chem Biol ; 1(1): 17-9, 2006 Feb 17.
Article in English | MEDLINE | ID: mdl-17163634

ABSTRACT

A recent publication revealing that the cytotoxic marine natural product pateamine A targets eukaryotic initiation factor eIF4A continues a story with lessons for both chemists and biologists, that is, the significance of natural products, the importance of synthetic organic chemistry, the small molecule regulation of eukaryotic translation machinery, and possibly a new approach to cancer chemotherapy.


Subject(s)
Epoxy Compounds/therapeutic use , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Macrolides/therapeutic use , Thiazoles/therapeutic use , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Epoxy Compounds/chemical synthesis , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Eukaryotic Initiation Factor-4A/drug effects , Eukaryotic Initiation Factor-4A/genetics , Macrolides/chemical synthesis , Macrolides/chemistry , Macrolides/pharmacology , Models, Genetic , Models, Molecular , Protein Biosynthesis/drug effects , RNA, Messenger/genetics , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacology
5.
Chem Biol ; 13(12): 1287-95, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17185224

ABSTRACT

Eukaryotic initiation factor 4A (eIF4A) is a member of the DEAD-box family of putative RNA helicases whose members are involved in many aspects of RNA metabolism. eIF4A is thought to facilitate binding of 43S preinitiation complexes to mRNAs by unwinding secondary structures present in the 5' untranslated region. Pateamine A, a small-molecule inhibitor of translation initiation, acts in an unusual manner by stimulating eIF4A activity. Herein, we report the elucidation of pateamine's mode of action. We demonstrate that Pateamine A is a chemical inducer of dimerization that forces an engagement between eIF4A and RNA and prevents eIF4A from participating in the ribosome-recruitment step of translation initiation.


Subject(s)
Epoxy Compounds/pharmacology , Eukaryotic Initiation Factor-4A/drug effects , Eukaryotic Initiation Factor-4A/metabolism , Macrolides/pharmacology , Protein Biosynthesis/physiology , RNA/metabolism , Thiazoles/pharmacology , Dimerization , Eukaryotic Initiation Factor-4G/drug effects , Eukaryotic Initiation Factor-4G/metabolism , Humans , Jurkat Cells , Multiprotein Complexes/drug effects , Multiprotein Complexes/metabolism , Protein Binding/physiology , Protein Biosynthesis/drug effects
6.
Mol Cell ; 20(5): 709-22, 2005 Dec 09.
Article in English | MEDLINE | ID: mdl-16337595

ABSTRACT

Translation initiation in eukaryotes is accomplished through the coordinated and orderly action of a large number of proteins, including the eIF4 initiation factors. Herein, we report that pateamine A (PatA), a potent antiproliferative and proapoptotic marine natural product, inhibits cap-dependent eukaryotic translation initiation. PatA bound to and enhanced the intrinsic enzymatic activities of eIF4A, yet it inhibited eIF4A-eIF4G association and promoted the formation of a stable ternary complex between eIF4A and eIF4B. These changes in eIF4A affinity for its partner proteins upon binding to PatA caused the stalling of initiation complexes on mRNA in vitro and induced stress granule formation in vivo. These results suggest that PatA will be a valuable molecular probe for future studies of eukaryotic translation initiation and may serve as a lead compound for the development of anticancer agents.


Subject(s)
Epoxy Compounds/pharmacology , Eukaryotic Cells/drug effects , Eukaryotic Initiation Factors/antagonists & inhibitors , Protein Biosynthesis/drug effects , Thiazoles/pharmacology , Epoxy Compounds/chemistry , Eukaryotic Cells/metabolism , Eukaryotic Initiation Factor-4A/drug effects , Eukaryotic Initiation Factor-4A/metabolism , Eukaryotic Initiation Factor-4G/drug effects , Eukaryotic Initiation Factor-4G/metabolism , Eukaryotic Initiation Factors/drug effects , Eukaryotic Initiation Factors/metabolism , HeLa Cells , Humans , In Vitro Techniques , Macrolides , Molecular Structure , Protein Biosynthesis/physiology , Thiazoles/chemistry
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