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Antiviral Research Apr 2022The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging...
The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation elongation factor 1 alpha) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Depsipeptides; Peptides, Cyclic; SARS-CoV-2; Vero Cells; Virus Replication; COVID-19 Drug Treatment
PubMed: 35231500
DOI: 10.1016/j.antiviral.2022.105270 -
Cancer Medicine Feb 2023Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with...
Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells. This phase I trial evaluated plitidepsin (3-h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4 weeks in 36 r/r MM patients. Twenty-two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose-limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0 mg/m , BTZ 1.3 mg/m , DXM 40.0 mg) was the RD for phase II studies. Results shown herein are focused on this RD. Two patients had DLTs (grade 3 diarrhea, and grade 3 nausea/vomiting refractory to antiemetic therapy). Grade ≥ 3 hematological toxicity (thrombocytopenia 46%, anemia 33%, and neutropenia 17%) was manageable and did not result in treatment discontinuation. Transient and manageable grade 3 ALT increase (26%) was the most common biochemical abnormality. At the RD cohort, overall response rate was 22.2% (95%CI, 6.4%-47.6%), including one stringent complete response, one very good partial response, and two partial responses in r/r patients to BTZ and/or lenalidomide. The clinical benefit rate was 77.8% (95%CI, 52.4-93.6%). No major pharmacokinetic drug-drug interaction was found. In conclusion, the triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r/r MM.
Topics: Adult; Humans; Multiple Myeloma; Bortezomib; Dexamethasone; Depsipeptides; Anemia; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 36127823
DOI: 10.1002/cam4.5250 -
Amino Acids Feb 2022COVID-19 has shaken all the countries across the globe and researchers are trying to find promising antiviral to cure the patients suffering from infection and can...
COVID-19 has shaken all the countries across the globe and researchers are trying to find promising antiviral to cure the patients suffering from infection and can decrease the death. Even, different nations are using repurposing drugs to cure the symptoms and these repurposing drugs are hydroxychloroquine, remdesivir, and lopinavir, and recently, India has recently given the approval for the 2-deoxy-D-glucose for emergency purpose to cure the patients suffering from the COVID-19. Plitidepsin is a popular molecule and can be used in treatment of myeloma. Plitidepsin was explored by scientists experimentally against the COVID-19 and was given to the patient. It is found to be more a promising repurposing drug against the COVID-19 than the remdesivir. Therefore, there is a need to understand the interaction of plitidepsin with the main protease of SARS-CoV-2. Molecular docking of the plitidepsin against Mpro of SARS-CoV-2 was performed and the binding energy was found to be - 137.992 kcal/mol. Furthermore, authors have performed the molecular dynamics simulations of the main protease of SARS-CoV-2 in presence of plitidepsin at 300 and 325 K. It was found that the plitidepsin binds effectively with the main protease of SARS-CoV-2 at 300 K.
Topics: Antiviral Agents; Coronavirus 3C Proteases; Depsipeptides; Drug Repositioning; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Peptides, Cyclic; Protease Inhibitors; Protein Binding; SARS-CoV-2
PubMed: 34807314
DOI: 10.1007/s00726-021-03098-1 -
Frontiers in Cellular and Infection... 2023The APLICOV-PC study assessed the safety and preliminary efficacy of plitidepsin in hospitalized adult patients with COVID-19. In this follow-up study (E-APLICOV), the...
INTRODUCTION
The APLICOV-PC study assessed the safety and preliminary efficacy of plitidepsin in hospitalized adult patients with COVID-19. In this follow-up study (E-APLICOV), the incidence of post-COVID-19 morbidity was evaluated and any long-term complications were characterized.
METHODS
Between January 18 and March 16, 2022, 34 of the 45 adult patients who received therapy with plitidepsin in the APLICOV-PC study were enrolled in E-APLICOV (median time from plitidepsin first dose to E-APLICOV enrollment, 16.8 months [range, 15.2-19.5 months]). All patients were functionally autonomous with regard to daily living (Barthel index: 100) and had normal physical examinations.
RESULTS
From the APLICOV-PC date of discharge to the date of the extension visit, neither Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5) grade 3-4 complications nor QT prolongation or significant electrocardiogram (EKG) abnormalities were reported. Five (14.7%) patients had another COVID-19 episode after initial discharge from APLICOV-PC, and in 2 patients (5.9%), previously unreported chest X-ray findings were documented. Spirometry and lung-diffusion tests were normal in 29 (85.3%) and 27 (79.4%) patients, respectively, and 3 patients needed additional oxygen supplementation after initial hospital discharge. None of these patients required subsequent hospital readmission for disease-related complications.
DISCUSSION
In conclusion, plitidepsin has demonstrated a favorable long-term safety profile in adult patients hospitalized for COVID-19. With the constraints of a low sample size and a lack of control, the rate of post-COVID-19 complications after treatment with plitidepsin is in the low range of published reports. (ClinicalTrials.gov Identifier: NCT05121740; https://clinicaltrials.gov/ct2/show/NCT05121740).
Topics: Humans; Adult; COVID-19; Follow-Up Studies; SARS-CoV-2; Hospitals; Treatment Outcome
PubMed: 36909731
DOI: 10.3389/fcimb.2023.1097809 -
Investigational New Drugs Oct 2017Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism...
Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. In total, a mean of 77.4% of the administered radioactivity was excreted over a time period of 20 days, of which 71.3% was recovered in faeces and 6.1% was found in urine. The majority excreted in urine was accounted for by unchanged plitidepsin, with only 1.5% of the total administered dose explained by metabolites in urine. Faeces, on the other hand contained low levels of parent compound, which means that most of the TRA excreted in faeces was accounted for by metabolites. TRA levels were 3.7 times higher in whole blood compared to plasma. Plitidepsin was widely distributed and plasma clearance was low. This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion.
Topics: Administration, Oral; Aged; Carbon Radioisotopes; Depsipeptides; Feces; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Peptides, Cyclic; Tissue Distribution
PubMed: 28111728
DOI: 10.1007/s10637-017-0432-5 -
Life Science Alliance Apr 2022Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation... (Randomized Controlled Trial)
Randomized Controlled Trial
Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.
Topics: Adult; Aged; COVID-19; Cell Line, Tumor; Depsipeptides; Drug Evaluation, Preclinical; Female; Hospitalization; Humans; Kaplan-Meier Estimate; Length of Stay; Male; Middle Aged; Neutropenia; Peptides, Cyclic; SARS-CoV-2; Treatment Outcome; Viral Load; COVID-19 Drug Treatment
PubMed: 35012962
DOI: 10.26508/lsa.202101200 -
Anticancer Research Sep 2021To evaluate the antitumor effects of Plitidepsin against clear cell carcinoma (CCC) of the ovary.
BACKGROUND/AIM
To evaluate the antitumor effects of Plitidepsin against clear cell carcinoma (CCC) of the ovary.
MATERIALS AND METHODS
The expression of eEF1A2 in ovarian cancer was assessed by immunohistochemistry. Using ovarian CCC cell lines, the antitumor effect of Plitidepsin was assessed both in vitro and in vivo. By over-expressing or knocking down the eEF1A2 expression, we investigated the role of eEF1A2 in the sensitivity of CCC cells to Plitidepsin.
RESULTS
Immunoreactivity to eEF1A2 was observed in 76.2% of CCC, which was significantly higher than other histological subtypes of ovarian cancer. Plitidepsin exhibited significant antitumor activity toward chemonaive and chemoresistant CCC cells both in vitro and in vivo. Ectopic expression of eEF1A2 in CCC cells resulted in increased sensitivity to Plitidepsin. In contrast, eEF1A2 knockdown decreased sensitivity of CCC cells to plitidepsin.
CONCLUSION
Plitidepsin, a novel anti-cancer agent that targets eEF1A2, may be a promising agent for treating ovarian CCC.
Topics: Adenocarcinoma, Clear Cell; Animals; Cell Line, Tumor; Cell Proliferation; Cisplatin; Depsipeptides; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mice; Ovarian Neoplasms; Peptide Elongation Factor 1; Peptides, Cyclic; Up-Regulation; Xenograft Model Antitumor Assays
PubMed: 34475047
DOI: 10.21873/anticanres.15232 -
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 -
Anti-cancer Drugs Mar 2015Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core... (Review)
Review
Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core ring structure. Many natural cyclic depsipeptides possessing intriguing structural and biological properties, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, and anti-inflammatory activities, have been identified from fungi, plants, and marine organisms. In particular, the potent effects of cyclic depsipeptides on tumor cells have led to a number of clinical trials evaluating their potential as chemotherapeutic agents. Although many of the trials have not achieved the desired results, romidepsin (FK228), a bicyclic depsipeptide that inhibits histone deacetylase, has been shown to have clinical efficacy in patients with refractory cutaneous T-cell lymphoma and has received Food and Drug Administration approval for use in treatment. In this review, we discuss antitumor cyclic depsipeptides that have undergone clinical trials and focus on their structural features, mechanisms, potential applications in chemotherapy, and pharmacokinetic and toxicity data. The results of this study indicate that cyclic depsipeptides could be a rich source of new cancer therapeutics.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Depsipeptides; Histone Deacetylase Inhibitors; Humans; Lactams; Lactones; Lymphoma, T-Cell, Cutaneous; Peptides, Cyclic
PubMed: 25419631
DOI: 10.1097/CAD.0000000000000183 -
Anti-cancer Drugs Mar 2017This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer...
This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (≥3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (≥3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasms; Niacinamide; Peptides, Cyclic; Phenylurea Compounds; Prospective Studies; Sorafenib; Young Adult; Gemcitabine
PubMed: 27977433
DOI: 10.1097/CAD.0000000000000457