-
Marine Drugs Aug 2021Worldwide, 19.3 million new cancer cases and almost 10.0 million cancer deaths occur each year. Recently, much attention has been paid to the ocean, the largest... (Review)
Review
Worldwide, 19.3 million new cancer cases and almost 10.0 million cancer deaths occur each year. Recently, much attention has been paid to the ocean, the largest biosphere of the earth that harbors a great many different organisms and natural products, to identify novel drugs and drug candidates to fight against malignant neoplasms. The marine compounds show potent anticancer activity in vitro and in vivo, and relatively few drugs have been approved by the U.S. Food and Drug Administration for the treatment of metastatic malignant lymphoma, breast cancer, or Hodgkin's disease. This review provides a summary of the anticancer effects and mechanisms of action of selected marine compounds, including cytarabine, eribulin, marizomib, plitidepsin, trabectedin, zalypsis, adcetris, and OKI-179. The future development of anticancer marine drugs requires innovative biochemical biology approaches and introduction of novel therapeutic targets, as well as efficient isolation and synthesis of marine-derived natural compounds and derivatives.
Topics: Animals; Antineoplastic Agents; Biological Products; Humans; Neoplasms; Seawater
PubMed: 34564150
DOI: 10.3390/md19090488 -
Chemistry & Biodiversity Feb 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication depends on the interaction between the viral proteins and the human translation machinery. The...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication depends on the interaction between the viral proteins and the human translation machinery. The cytotoxic peptide plitidepsin was found to inhibit CoV-2 up to 90 % at a concentration of 0.88 nM. In vitro studies suggest that this activity may be attributed to the inhibition of the eukaryotic translation elongation factor 1A (eEF1A). However, recent reports raised the potential for other cellular targets which plitidepsin may use to exert its potent antiviral activity. The lack of data about these potential targets represents a major limitation for its structural optimization. This work describes the use of a molecular modeling approach to rationalize the in vitro antiviral activity of plitidepsin and to identify potential cellular targets. The developed protocol involves an initial molecular docking step followed by molecular dynamics and binding free energy calculations. The results reveal the potential for plitidepsin to bind to the active site of the key enzyme SARS-CoV-2 RdRp. The results also highlight the importance of van der Waals interactions for proper binding with the enzyme. We believe that the results presented in this study could provide the grounds for the optimization of plitidepsin analogs as SARS-CoV-2 inhibitors.
Topics: Antiviral Agents; COVID-19; Depsipeptides; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Peptides, Cyclic; SARS-CoV-2
PubMed: 34813168
DOI: 10.1002/cbdv.202100719 -
Marine Drugs Feb 2021The latest chapter of the historic battle of humans against pathogenic microbes is the severe acute respiratory syndrome (SARS)-like coronavirus-2 (SARS-CoV-2),...
The latest chapter of the historic battle of humans against pathogenic microbes is the severe acute respiratory syndrome (SARS)-like coronavirus-2 (SARS-CoV-2), responsible for COVID-19, a respiratory disease declared a global pandemic by the WHO on March 11, 2020 [...].
Topics: Anti-Inflammatory Agents; Antimicrobial Cationic Peptides; Antiviral Agents; Aquatic Organisms; Biological Products; COVID-19; COVID-19 Vaccines; Depsipeptides; Humans; Pandemics; Peptides, Cyclic; SARS-CoV-2; Seawater; Virus Attachment; COVID-19 Drug Treatment
PubMed: 33670191
DOI: 10.3390/md19020104 -
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 -
Revista Espanola de Quimioterapia :... Oct 2021The knowledge of the replicative cycle of SARS-CoV-2 and its interactions with cellular proteins has opened a new therapeutic possibility based on blocking those... (Review)
Review
[Plitidepsin, an inhibitor of the cell elongation factor eEF1a, and molnupiravir an analogue of the ribonucleoside cytidine, two new chemical compounds with intense activity against SARS-CoV-2].
The knowledge of the replicative cycle of SARS-CoV-2 and its interactions with cellular proteins has opened a new therapeutic possibility based on blocking those essential for the virus. The cellular protein elongation factor eEF1A could be a good target. Among its natural inhibitors are didemnins and their related chemical compounds such as plitidepsin. In human cell culture, this compound is capable of inhibiting the virus with a potency 27,5 times that of remdesivir. It must be administered intravenously. Of the ribonucleoside analogues, molnupiravir (MK-4483/EIDD-2801) (hydroxy-cytidine) determines a lethal mutagenesis on SARS-CoV-2. In animals, after oral administration, the pulmonary viral load decreases 25,000 times and when administered as prophylaxis, approximately 100,000 times. It prevents the transmission of the virus and eliminates its presence in the oropharynx. Both chemicals have started Phase I / II human clinical trials.
Topics: Animals; Antiviral Agents; COVID-19; Cytidine; Depsipeptides; Humans; Hydroxylamines; Peptide Elongation Factors; Peptides, Cyclic; Ribonucleosides; SARS-CoV-2
PubMed: 33902254
DOI: 10.37201/req/042.2021 -
Journal of Hematology & Oncology Jan 2022There is an urgent need for highly efficacious antiviral therapies in immunosuppressed hosts who develop coronavirus disease (COVID-19), with special concern for those...
Plitidepsin as a successful rescue treatment for prolonged viral SARS-CoV-2 replication in a patient with previous anti-CD20 monoclonal antibody-mediated B cell depletion and chronic lymphocytic leukemia.
BACKGROUND
There is an urgent need for highly efficacious antiviral therapies in immunosuppressed hosts who develop coronavirus disease (COVID-19), with special concern for those affected by hematological malignancies.
CASE PRESENTATION
Here, we report the case of a 75-year-old male with chronic lymphocytic leukemia who was deficient in CD19CD20 B-lymphocyte populations due to previous treatment with anti-CD20 monoclonal antibodies. The patient presented with severe COVID-19 pneumonia due to prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and was treated with two courses of the antiviral plitidepsin on a compassionate use basis. The patient subsequently achieved an undetectable viral load, and his pneumonia resolved.
CONCLUSIONS
Treatment with plitidepsin was well-tolerated without any further hematological or cardiovascular toxicities. This case further supports plitidepsin as a potential antiviral drug in SARS-CoV-2 patients affected by immune deficiencies and hematological malignancies.
Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; B-Lymphocytes; COVID-19; Depsipeptides; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Depletion; Male; Peptides, Cyclic; SARS-CoV-2; Treatment Outcome; Virus Replication
PubMed: 35012608
DOI: 10.1186/s13045-021-01220-0 -
Science (New York, N.Y.) Feb 2021
Topics: Depsipeptides; Host-Pathogen Interactions; Humans; Peptides, Cyclic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33632832
DOI: 10.1126/science.abg6837 -
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 -
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 -
EClinicalMedicine Jun 2022The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19...
BACKGROUND
The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19 pneumonia who were not vaccinated, or with a complete or incomplete vaccination schedule.
METHODS
This COVID-19 specialized single-center cohort study of 1888 COVID-19 patients hospitalized at the "Enfermera Isabel Zendal" Emergencies Hospital (HEEIZ), Madrid (Spain) was performed between July 1 and September 30, 2021. It compared the results of 1327 hospitalized unvaccinated patients to 209 hospitalized fully vaccinated and 352 hospitalized partially vaccinated patients. The four different COVID-19 vaccines authorized in Spain during the time-period studied were: BNT162b2 (Pfizer); ChAdOx1 nCoV-19 (AstraZeneca), mRNA-1273 (Moderna); Ad26.COV2.S (Janssen).
FINDINGS
Hospitalized patients' median age was 41 years (IQR 33-50) for the unvaccinated and 61 years (IQR 53-67) for the fully vaccinated ones. The main comorbidities were obesity, hypertension and diabetes mellitus. 20% of unvaccinated patients (266) required noninvasive respiratory care, as did 14% (51) of partially and 14% (30) of fully vaccinated; 6% (78) of the unvaccinated patients also needed invasive respiratory care, as did 5% (16) of partially and 11 (5%) fully vaccinated.
INTERPRETATION
Fully vaccinated patients were 84% (95% CI: 82-86%) less likely to be admitted to hospital, and protection rose for those aged <50 years. Once hospitalized, vaccinated patients displayed more protection against requiring respiratory care than unvaccinated ones, despite being older and having more comorbidities. No differences appeared for the four studied COVID-19 vaccines and complying with vaccination recommendations proved relevant.
FUNDING
The research was funded by the "Plan Propio de Investigación" Program of the Castilla-La Mancha University /European Regional Development Fund (2021-GRIN-31,039).
PubMed: 35611064
DOI: 10.1016/j.eclinm.2022.101453