-
Annals of Oncology : Official Journal... Oct 2021
Topics: Antineoplastic Agents; Depsipeptides; Humans; Neoplasms; Peptides, Cyclic; COVID-19 Drug Treatment
PubMed: 34242743
DOI: 10.1016/j.annonc.2021.07.003 -
Metabolism Open Jun 2021Remdesivir (GS-5734), a drug initially developed to treat hepatitis C and Ebola virus disease, was the first approved treatment for severe coronavirus disease 2019...
Remdesivir (GS-5734), a drug initially developed to treat hepatitis C and Ebola virus disease, was the first approved treatment for severe coronavirus disease 2019 (COVID-19). However, apart from remdesivir, there is a paucity of other specific anti-viral agents against SARS-CoV-2 infection. In 2017, researchers had documented the anti-coronavirus potential of remdesivir in animal models. At the same time, trials performed during two Ebola outbreaks in Africa showed that the drug was safe. Although vaccines against SARS-CoV-2 infection have emerged at an enormously high speed, equivalent results from efforts towards the development of anti-viral drugs, which could have played a truly life-saving role in the current stage of the pandemic, have been stagnating. In this review, we will focus on the current treatment options for COVID-19 which mainly consist of repurposed agents or treatments conferring passive immunity (convalescent plasma or monoclonal antibodies). Additionally, potential specific anti-viral therapies under development will be reviewed, such as the decoy miniprotein CTC-445.2d, protease inhibitors, mainly against the Main protein Mpro, nucleoside analogs, such as molnupiravir and compounds blocking the replication transcription complex proteins, such as zotatifin and plitidepsin. These anti-viral agents seem to be very promising but still require meticulous clinical trial testing in order to establish their efficacy and safety. The continuous emergence of viral variants may pose a real challenge to the scientific community towards that end. In this context, the advent of nanobodies together with the potential administration of a combination of anti-viral drugs could serve as useful tools in the armamentarium against COVID-19.
PubMed: 34056571
DOI: 10.1016/j.metop.2021.100096 -
Pharmacological Research Jun 2024Eukaryotic elongation factor 1A (eEF1A) is among the most abundant proteins in eukaryotic cells. Evolutionarily conserved across species, eEF1A is in charge of... (Review)
Review
Eukaryotic elongation factor 1A (eEF1A) is among the most abundant proteins in eukaryotic cells. Evolutionarily conserved across species, eEF1A is in charge of translation elongation for protein biosynthesis as well as a plethora of non-translational moonlighting functions for cellular homeostasis. In malignant cells, however, eEF1A becomes a pleiotropic driver of cancer progression via a broad diversity of pathways, which are not limited to hyperactive translational output. In the past decades, mounting studies have demonstrated the causal link between eEF1A and carcinogenesis, gaining deeper insights into its multifaceted mechanisms and corroborating its value as a prognostic marker in various cancers. On the other hand, an increasing number of natural and synthetic compounds were discovered as anticancer eEF1A-targeting inhibitors. Among them, plitidepsin was approved for the treatment of multiple myeloma whereas metarrestin was currently under clinical development. Despite significant achievements in these two interrelated fields, hitherto there lacks a systematic examination of the eEF1A protein in the context of cancer research. Therefore, the present work aims to delineate its clinical implications, molecular oncogenic mechanisms, and targeted therapeutic strategies as reflected in the ever expanding body of literature, so as to deepen mechanistic understanding of eEF1A-involved tumorigenesis and inspire the development of eEF1A-targeted chemotherapeutics and biologics.
Topics: Humans; Peptide Elongation Factor 1; Neoplasms; Animals; Antineoplastic Agents; Molecular Targeted Therapy; Clinical Relevance
PubMed: 38677532
DOI: 10.1016/j.phrs.2024.107195 -
The Journal of Biological Chemistry Mar 2024Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we...
Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we identified EEF1A1 as a mediator of lipotoxicity and demonstrated that chemical inhibition of EEF1A1 activity reduced mouse liver lipid accumulation. These findings suggested a link between EEF1A1 and metabolism. Therefore, we investigated its role in regulating metabolic substrate preference. EEF1A1-deficient Chinese hamster ovary (2E2) cells displayed reduced media lactate accumulation. These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells and in WT Chinese hamster ovary and HepG2 cells treated with selective EEF1A inhibitors, didemnin B, or plitidepsin. Extracellular flux analyses revealed decreased glycolytic ATP production and increased mitochondrial-to-glycolytic ATP production ratio in 2E2 cells, suggesting a more oxidative metabolic phenotype. Correspondingly, fatty acid oxidation was increased in 2E2 cells. Both 2E2 cells and HepG2 cells treated with didemnin B exhibited increased neutral lipid content, which may be required to support elevated oxidative metabolism. RNA-seq revealed a >90-fold downregulation of a rate-limiting glycolytic enzyme, hexokinase 2, which we confirmed through immunoblotting and enzyme activity assays. Pathway enrichment analysis identified downregulations in TNFA signaling via NFKB and MYC targets. Correspondingly, nuclear abundances of RELB and MYC were reduced in 2E2 cells. Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells.
Topics: Animals; Cricetinae; Humans; Adenosine Triphosphate; Cell Line; Cricetulus; Hexokinase; Lipids; Peptide Elongation Factor 1; Glycolysis; Oxidation-Reduction; Cell Movement; Cell Proliferation; Lipid Metabolism
PubMed: 38272231
DOI: 10.1016/j.jbc.2024.105684 -
Molecules (Basel, Switzerland) Feb 2021Currently, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has infected people among all countries and is a pandemic as declared by the World Health...
Currently, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has infected people among all countries and is a pandemic as declared by the World Health Organization (WHO). SARS-CoVID-2 main protease is one of the therapeutic drug targets that has been shown to reduce virus replication, and its high-resolution 3D structures in complex with inhibitors have been solved. Previously, we had demonstrated the potential of natural compounds such as serine protease inhibitors eventually leading us to hypothesize that FDA-approved marine drugs have the potential to inhibit the biological activity of SARS-CoV-2 main protease. Initially, field-template and structure-activity atlas models were constructed to understand and explain the molecular features responsible for SARS-CoVID-2 main protease inhibitors, which revealed that Eribulin Mesylate, Plitidepsin, and Trabectedin possess similar characteristics related to SARS-CoVID-2 main protease inhibitors. Later, protein-ligand interactions are studied using ensemble molecular-docking simulations that revealed that marine drugs bind at the active site of the main protease. The three-dimensional reference interaction site model (3D-RISM) studies show that marine drugs displace water molecules at the active site, and interactions observed are favorable. These computational studies eventually paved an interest in further in vitro studies. Finally, these findings are new and indeed provide insights into the role of FDA-approved marine drugs, which are already in clinical use for cancer treatment as a potential alternative to prevent and treat infected people with SARS-CoV-2.
Topics: Catalytic Domain; Depsipeptides; Drug Repositioning; Furans; Humans; Ketones; Models, Molecular; Molecular Docking Simulation; Peptide Hydrolases; Peptides, Cyclic; Quantitative Structure-Activity Relationship; SARS-CoV-2; Serine Proteinase Inhibitors; Trabectedin; Viral Proteins; Virus Replication
PubMed: 33578831
DOI: 10.3390/molecules26040936 -
Cold Spring Harbor Molecular Case... Feb 2020-rearranged sarcomas (CRSs) have recently been characterized as a distinct sarcoma subgroup with a less favorable prognosis compared to other small round cell sarcomas....
-rearranged sarcomas (CRSs) have recently been characterized as a distinct sarcoma subgroup with a less favorable prognosis compared to other small round cell sarcomas. CRSs share morphologic features with Ewing's sarcoma and prior to 2013 were grouped under undifferentiated sarcomas with round cell phenotype by the WHO classification. In this report, whole-genome sequencing and RNA sequencing were performed for an adolescent male patient with CRS who was diagnosed with undifferentiated pleomorphic sarcoma (UPS) by three contemporary institutions. Somatic mutation analysis identified mutations in , , and in pre- and post-treatment tissue samples, as well as a fusion that was confirmed by qPCR and DUX4 immunohistochemistry. Of particular interest was the overexpression of the translation factor , which has oncogenic properties and has recently been identified as a target of the investigational agent plitidepsin. This case may provide a valuable waypoint in the understanding and classification of CRSs and may provide a rationale for targeting eEF1A1 in similar soft tissue sarcoma cases.
Topics: Alleles; Biomarkers, Tumor; Biopsy; Child; Chromosome Mapping; Computational Biology; Gene Expression; Genomics; HLA Antigens; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Neoplasm Grading; Oncogene Proteins, Fusion; Sarcoma, Small Cell; Symptom Assessment; Translocation, Genetic; Whole Genome Sequencing
PubMed: 32014859
DOI: 10.1101/mcs.a004812 -
A Selective SARS-CoV-2 Host-Directed Antiviral Targeting Stress Response to Reactive Oxygen Species.ACS Central Science Jan 2023The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) catalyzed the development of vaccines and antivirals. Clinically approved drugs against...
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) catalyzed the development of vaccines and antivirals. Clinically approved drugs against SARS-CoV-2 target the virus directly, which makes them susceptible to viral mutations, which in turn can attenuate their antiviral activity. Here we report a host-directed antiviral (HDA), piperlongumine (PL), which exhibits robust antiviral activity as a result of selective induction of reactive oxygen species in infected cells by GSTP1 inhibition. Using a transgenic K18-hACE2 mouse model, we benchmarked PL against plitidepsin, a HDA undergoing phase III clinical trials. We observed that intranasal administration of PL is superior in delaying disease progression and reducing lung inflammation. Importantly, we showed that PL is effective against several variants of concern (VOCs), making it an ideal pan-variant antiviral. PL may display a critical role as an intranasal treatment or prophylaxis against a range of viruses, expanding the arsenal of tools to fight future outbreaks.
PubMed: 36712488
DOI: 10.1021/acscentsci.2c01243