A5012685219- Chemical Synthesis and Analysis
- Latin American Literature Studies
- interferon and immune responses
- Marine Sponges and Natural Products
- Cultural and Social Studies in Latin America
- Endoplasmic Reticulum Stress and Disease
- Microbial Natural Products and Biosynthesis
- Literary and Cultural Studies
- Literature, Culture, and Aesthetics
- Synthesis and Biological Activity
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- Latin American Literature Analysis
- Neonatal Respiratory Health Research
- Cancer-related Molecular Pathways
- Influenza Virus Research Studies
- Lung Cancer Research Studies
- Congenital Diaphragmatic Hernia Studies
- Respiratory viral infections research
- Mass Spectrometry Techniques and Applications
- Protein Kinase Regulation and GTPase Signaling
- Bioactive Compounds and Antitumor Agents
- Cell death mechanisms and regulation
- Biological Activity of Diterpenoids and Biflavonoids
- Philosophical Thought and Analysis
PharmaMar (Spain)
2014-2025
Hospital Universitario La Paz
1999-2000
Instituto de Investigaciones Biomédicas Sols-Morreale
2000
Freie Universität Berlin
1979
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of have potent antiviral effects. We found that drug plitidepsin (aplidin), which has limited clinical approval, possesses activity (90% inhibitory concentration = 0.88 nM) is more than remdesivir against SARS-CoV-2 in vitro by a factor 27.5, toxicity cell culture. Through use drug-resistant mutant, we show mediated through inhibition known target...
Plitidepsin is an antitumoral compound safe for treating COVID-19 that targets the translation elongation factor eEF1A. Here we detect plitidepsin decreases de novo cap-dependent of SARS-CoV-2 and non-viral RNAs but affects less than 13% host proteome, thus preserving cellular viability. In response to plitidepsin, cells upregulate EIF2AK3 proteins reduce translation, also support proteostasis via ribosome synthesis cap-independent by eIF4G2 IGF2BP2. While inhibits cap- or internal entry...
We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin specific cellular stress response program, including sustained activation the epidermal factor receptor (EGFR), non-receptor protein-tyrosine kinase Src, serine/threonine kinases JNK p38 MAPK. Aplidin-induced was only partially blocked by general caspase inhibitor...
Abstract eEF1A2 is one of the isoforms alpha subunit eukaryotic Elongation Factor 1. It overexpressed in human tumors and endowed with oncogenic properties, favoring tumor cell proliferation while inhibiting apoptosis. We demonstrate that plitidepsin, an antitumor agent marine origin has successfully completed a phase-III clinical trial for multiple myeloma, exerts its activity by targeting eEF1A2. The drug interacts K D 80 nM target residence time circa 9 min. This protein was also...
DNA topoisomerase 1 (TOP1) is essential for transcription, replication, and repair. Its function relies on two catalytic steps, breakage rejoining. Inhibitors of the second step prevent rejoining lead to persistent breaks, acting as poisons, used anticancer drugs. However, reliable inhibitors first are not available. Here, we provide genetic molecular evidence supporting that Patulin and, a lesser extent, Xestoquinol inhibit TOP1 in vitro, yeast human cells. Particularly, prevents...
Through several not-fully-characterised moonlighting functions, translation elongation factor eEF1A2 is known to provide a fitness boost cancer cells. Furthermore, has been demonstrated confer neoplastic characteristics on preneoplastic, nontumourigenic precursor We have previously shown that the target of plitidepsin, marine drug currently in development for treatment. Herein, we characterised new signalling pathway through which promotes tumour cell survival. Previously unknown binding...
The pandemic caused by the new coronavirus SARS-CoV-2 has made evident need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that also shown a potent pre-clinical efficacy against SARS-CoV-2. targets host protein eEF1A (eukaryotic translation elongation factor 1 alpha) affects viral infection at early, post-entry step. Because electron microscopy valuable tool study virus-cell interactions...
Gastric cancer continues to be a major global health challenge due its high mortality rate, with over half of patients showing significant dysregulation the WNT/β-catenin pathway. Ecubectedin, novel transcriptional inhibitor, has shown potent antiproliferative effects across several solid tumors. The aim this study was characterize molecular ecubectedin in gastric cancer, both vitro and vivo, focusing on transcriptomic analysis key regulatory pathways. Ecubectedin´s antineoplastic activity...
The thyroid transcription factor (TTF)-1 has an essential role in lung morphogenesis and development. It is involved the of surfactant proteins (SP), which are critical respiratory function. Neonates with congenital diaphragmatic hernia die failure caused by pulmonary hypoplasia associated biochemical immaturity. To gain new insights into causes this disorder effect prenatal hormonal treatment on reducing mortality these infants, we evaluated expression TTF-1 as marker SP-B maturity. Using a...
Four new antitumor pyranones, PM050511 (1), PM050463 (2), PM060054 (3), and PM060431 (4), were isolated from the cell extract of marine-derived Streptomyces albus POR-04-15-053. Their structures elucidated by a combination spectroscopic methods, mainly 1D 2D NMR HRESIMS. They consist an α-methoxy-γ-pyrone ring containing highly substituted tetraene side chain glycosylated at C-10 in case 1 4. Compounds 4 displayed strong cytotoxicity against three human tumor lines with GI50 values...
Aplidin (APL) is a new antitumoral drug from marine origin currently in phase II clinical trials against wide multiplicity of cancers. As resistance may be, as with other drugs, an important obstacle to the APL therapeutic efficacy, we have established acquired cellular model by continuous exposure HeLa cells drug. The stably resistant subline generated (HeLa-APL), possessing more than 1000-fold relative parental cells, did not show crossresistance subset clinically relevant agents. In...
The isolation, structural characterization and cytotoxic properties of three new (1-3) known (4-6) gracilins, obtained from the sponge Spongionella pulchella is described. Gracilin B (4) exhibited selective, broad spectrum inhibition integrin-mediated cell adhesion to a variety physiological substrates. Keywords: Sponge metabolites, Gracilin, pulchella, Anticancer agent, Integrin, Adhesion inhibitor
Abstract The design of living cell studies aimed at deciphering the mechanism action drugs targeting proteins with multiple functions, expressed in a wide range concentrations and cellular locations, is real challenge. We recently showed that antitumor drug plitidepsin (APL) localizes sufficiently close to elongation factor eEF1A2 so as suggest formation drug-protein complexes cells. Here we present an extension our previous micro-spectroscopy study, combines Generalized Polarization ( GP )...
Abstract Aplidin is a cyclic depsipeptide of the family didemnins, originally isolated from colonial tunicate Aplidium albicans. being evaluated in phase III clinical trial patients with relapse or refractory multiple myeloma. As part its antitumor activity, induces rapid oxidative stress, activation Rac1 and phosphorylation p38 JNK1 stress kinases, which together trigger apoptotic death tumor cells. Didemnin B (DB), molecule closely related to Aplidin, has been previously shown interact...
Abstract Eukaryotic Elongation Factor 1A2 (eEF1A2) is an isoform of the alpha subunit eEF1 complex. Differently from A1 isoform, expression eEF1A2 restricted to brain, heart and skeletal muscle. overexpressed in tumors, including multiple myeloma (MM) (Li et al, 2012, PLOS One 5, e10755), prostate (Sun 2014, Biochem Biophys Res Commun 450:1-6), pancreas (Xu 2013, Clin Exp Metastasis 30:933-44) ovarian (Anand 2002, Nat Genet 31:301-5), has also oncogenic behavior favoring tumor cell...
Abstract Plitidepsin is a host-targeted compound known for inducing strong anti–SARS-CoV-2 activity, as well having the capacity of reducing lung inflammation. Because IL-6 one main cytokines involved in acute respiratory distress syndrome, effect plitidepsin secretion different vitro and vivo experimental models was studied. A plitidepsin-mediated reduction found human monocyte-derived macrophages exposed to nonproductive SARS-CoV-2. In resiquimod (a ligand TLR7/8)–stimulated THP1...
In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a cyclic depsipeptide, PM170453 (1), cyanobacterium of the genus Lyngbya sp., collected in Indo-Pacific Ocean. Structure elucidation compound was determined by spectroscopic methods including MS, 1H, 13C and 2D-NMR. To solve supply problem 1 progress pharmaceutical development, total synthesis that involves 20 steps convergent process carried out. Its vitro cytotoxic activity...