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Science (New York, N.Y.) Feb 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; COVID-19; Coronavirus Nucleocapsid Proteins; Depsipeptides; Drug Evaluation, Preclinical; Female; HEK293 Cells; Humans; Lung; Mice, Inbred C57BL; Mutation; Peptide Elongation Factor 1; Peptides, Cyclic; Phosphoproteins; RNA, Viral; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment; Mice
PubMed: 33495306
DOI: 10.1126/science.abf4058 -
Marine Drugs Dec 2020The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental... (Review)
Review
The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use.
Topics: Animals; Antineoplastic Agents; Aquatic Organisms; Biological Products; Drug Discovery; Humans; Marine Toxins; Neoplasms; Water Microbiology
PubMed: 33291602
DOI: 10.3390/md18120619 -
Natural Product Reports Jun 2020Covering: 2000 to 2020 The translation of mRNA into proteins is a precisely regulated, complex process that can be divided into three main stages, i.e. initiation,... (Review)
Review
Covering: 2000 to 2020 The translation of mRNA into proteins is a precisely regulated, complex process that can be divided into three main stages, i.e. initiation, elongation, termination, and recycling. This contribution is intended to highlight how natural products interfere with the elongation phase of eukaryotic protein biosynthesis. Cycloheximide, isolated from Streptomyces griseus, has long been the prototype inhibitor of eukaryotic translation elongation. In the last three decades, a variety of natural products from different origins were discovered to also address the elongation step in different manners, including interference with the elongation factors eEF1 and eEF2 as well as binding to A-, P- or E-sites of the ribosome itself. Recent advances in the crystallization of the ribosomal machinery together with natural product inhibitors allowed characterizing similarities as well as differences in their mode of action. Since aberrations in protein synthesis are commonly observed in tumors, and malfunction or overexpression of translation factors can cause cellular transformation, the protein synthesis machinery has been realized as an attractive target for anticancer drugs. The therapeutic use of the first natural products that reached market approval, plitidepsin (Aplidin®) and homoharringtonine (Synribo®), will be introduced. In addition, we will highlight two other potential indications for translation elongation inhibitors, i.e. viral infections and genetic disorders caused by premature termination of translation.
Topics: Antineoplastic Agents; Biological Products; Cycloheximide; Humans; Peptide Chain Elongation, Translational; Peptide Elongation Factor 1; Protein Synthesis Inhibitors; Ribosomes
PubMed: 32428051
DOI: 10.1039/d0np00011f -
Drugs of Today (Barcelona, Spain : 1998) May 2020While remaining relatively rare, multiple myeloma (MM) accounts for approximately 10% of all hematological malignancies, being an insidious disease with an overall...
While remaining relatively rare, multiple myeloma (MM) accounts for approximately 10% of all hematological malignancies, being an insidious disease with an overall 5-year survival rate of 52%. In addition to other associated complications, myeloma bone disease further aggravates MM patients, the majority of whom suffer from lytic lesions, leading to pain, fractures, mobility issues and neurological deficits. Patients not responding or becoming resistant to prior therapies have now a novel therapeutic tool with an unprecedent mode of action, differing from those currently in use. The anticancer effects of the marine-derived antitumor agent plitidepsin primarily rely on the interaction with elongation factor 1-α 2 (eEF1A2), known to be overexpressed in breast cancer and MM cells, targeting the noncanonical role of the protein and leading to a proapoptotic response. Following the drug's approval from Australian regulatory authorities, eligible patients will have access to a new first-in-class drug to treat MM, expanding the current anti-MM portfolio. Plitidepsin (Aplidin; PharmaMar) was approved in combination with the corticosteroid agent dexamethasone, to treat MM patients who failed or became resistant to other therapies, covering the third- and fourth-line treatment setting.
Topics: Antineoplastic Agents; Australia; Depsipeptides; Humans; Multiple Myeloma; Peptide Elongation Factor 1; Peptides, Cyclic
PubMed: 32406881
DOI: 10.1358/dot.2020.56.5.3135886 -
Developmental and Comparative Immunology Jul 2020Among the diseases that afflict the human population, cancer is one for which many drug treatments are not yet known or effective. Moreover, the pharmacological... (Review)
Review
Among the diseases that afflict the human population, cancer is one for which many drug treatments are not yet known or effective. Moreover, the pharmacological treatments used often create serious side effects in sick patients and for this reason, it is essential to find effective and less harmful treatments. To date, marine biodiversity is a real source of metabolites with antitumoral activity and among invertebrates' ascidians have been the main source to obtain them. Mediterranean area is the richest in biodiversity and contains several ascidian species used in drugs development during the years. However, many more Mediterranean ascidian species have not been studied and could be a source of useful bioactive compounds. This review aims to summarize the scientific studies that analyzed the antitumor compounds obtained from different Mediterranean ascidians species, encouraging them to search further compounds in other new species to improve pharmacological treatments and human population life.
Topics: Animals; Antineoplastic Agents; Biological Products; Depsipeptides; Humans; Mediterranean Sea; Neoplasms; Peptides, Cyclic; Trabectedin; Urochordata
PubMed: 32192994
DOI: 10.1016/j.dci.2020.103669 -
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 -
Biochemical Pharmacology Feb 2020Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory...
Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory authorities for the treatment of multiple myeloma patients. Plitidepsin binds to eEF1A2 and induces oxidative stress, Rac1 activation and JNK1 phosphorylation, triggering a rapid apoptotic program in tumor cells. Since oxidative stress is one of the known sources of endoplasmic reticulum stress, we investigated whether PLD was inducing a bona fide ER stress in HeLa cells and whether this process was essential in the mechanism of action of the compound. Indeed, PLD activated an ER stress-induced unfolded protein response (UPR), including the alternative splicing of XBP1, the proteolytic processing of ATF6 and the phosphorylation of eIF2α and JNK. Interestingly, though PLD induced a strong phosphorylation of eIF2α in all the analyzed cell lines, it did not elicit an increased expression of ATF4 and CHOP, a transcription factor involved in launching UPR-mediated apoptosis. On the contrary, a clear reduction of CHOP protein levels was observed after PLD treatment, most probably due to both the lack of transactivation by ATF4 and its rapid degradation by the ubiquitin/proteasome machinery. Using fibroblasts devoid of each one of the four possible kinases involved in eIF2α phosphorylation, we observed that only PKR was involved in the response to PLD treatment and, accordingly, PKR fibroblasts are shown to be resistant to the apoptogenic activity of the compound. Furthermore, eIF2α phosphorylation itself was shown to be irrelevant for the induction of cell death by PLD. Instead, we reveal that PLD induces an increase in the levels of misfolded proteins while simultaneously inhibiting the autophagic flux. These two effects combined prevent PLD-treated cells from reducing proteotoxic stress and lead to apoptosis. Other anti-myeloma drugs like bortezomib, which target the proteasome, also inhibit the degradation of misfolded proteins through alternate pathways and a synergistic anticancer effect of the PLD plus bortezomib combination has been previously disclosed. The present results extend this synergy to in vivo experiments and provide a mechanistic rationale for this synergy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Depsipeptides; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, SCID; Multiple Myeloma; Neoplasms, Experimental; Oxidative Stress; Peptides, Cyclic; Phosphorylation; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Transcription Factor CHOP
PubMed: 31812675
DOI: 10.1016/j.bcp.2019.113744 -
Australian Prescriber Oct 2019
Review
PubMed: 31631934
DOI: 10.18773/austprescr.2019.059 -
British Journal of Pharmacology Jan 2020Marine natural products have proven, over the last half-century, to be effective biological modulators. These molecules have revealed new targets for cancer therapy as... (Review)
Review
Marine natural products have proven, over the last half-century, to be effective biological modulators. These molecules have revealed new targets for cancer therapy as well as dissimilar modes of action within typical classes of drugs. In this scenario, innovation from marine-based pharmaceuticals has helped advance cancer chemotherapy in many aspects, as most of these are designated as first-in-class drugs. Here, by examining the path from discovery to development of clinically approved drugs of marine origin for cancer treatment-cytarabine (Cytosar-U®), trabectedin (Yondelis®), eribulin (Halaven®), brentuximab vedotin (Adcetris®), and plitidepsin (Aplidin®)- together with those in late clinical trial phases-lurbinectedin, plinabulin, marizomib, and plocabulin-the present review offers a critical analysis of the contributions given by these new compounds to cancer pharmacotherapy.
Topics: Animals; Antineoplastic Agents; Biological Products; Clinical Trials as Topic; Cytarabine; Drug Discovery; Furans; Humans; Ketones; Neoplasms; Porifera; Trabectedin
PubMed: 31621891
DOI: 10.1111/bph.14876 -
Computational Biology and Chemistry Dec 2019The low molecular weight protein tyrosine phosphatase (LMW-PTP) could regulate many signaling pathways, and it had drawn attention as a potential target for cancer. As...
The low molecular weight protein tyrosine phosphatase (LMW-PTP) could regulate many signaling pathways, and it had drawn attention as a potential target for cancer. As previous report has indicated that the aplidin could inhibit the LMW-PTP, and thus, the relevant cancer caused by the abnormal regulation of the LMW-PTP could be remission. However, the molecular mechanism of inhibition of the LMW-PTP by the aplidin had not been fully understood. In this study, various computational approaches, namely molecular docking, MDs and post-dynamic analyses were utilized to explore the effect of the aplidin on the LMW-PTP. The results suggested that the intramolecular interactions of the residues in the two sides of the active site (Ser43-Ala55 and Pro121-Asn134) and the P-loop region (Leu13-Ser19) in the LMW-PTP was disturbed owing to the aplidin, meanwhile, the π-π interaction between Tyr131 and Tyr132 might be broken. The Asn15 might be the key residue to break the residues interactions. In a word, this study may provide more information for understanding the effect of inhibition of the aplidin on the LMW-PTP.
Topics: Catalytic Domain; Depsipeptides; Enzyme Inhibitors; Humans; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Weight; Peptides, Cyclic; Protein Tyrosine Phosphatases
PubMed: 31561070
DOI: 10.1016/j.compbiolchem.2019.107123