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The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet promising magic bullets still do not exist. Numerous natural products (cordycepin, gallinamide A, plitidepsin, telocinobufagin, and tylophorine) have been widely studied and play a potential function in treating COVID-19. In this paper, we reviewed published studies (from May 2021 to April 2022) relating closely to bioactive natural products (isolated from medicinal plants, animals products, and marine organisms) in COVID-19 therapy in vitro to provide some essential guidance for anti-SARS-CoV-2 drug research and development.

Plitidepsin (P) is a marine-derived anticancer compound isolated from the tunicate Aplidium albicans . P plus low-dose dexamethasone (LD-DXM) was evaluated versus LD-DXM alone in patients with relapsed/refractory multiple myeloma (r/r MM) in the randomized phase III ADMYRE trial. In absence of a randomized study with P + LD-DXM vs. POM + LD-DXM, a direct matched comparison between P + LD-DXM (ADMYRE data) and pomalidomide (POM) + LD-DXM as an External Control Arm (ECA) was conducted using individual patient-level data from several contemporary POM + LD-DXM trials with a similar design. A first analysis (ECA1) showed that P + LD-DXM was non-inferior to POM + LD-DXM in terms of median overall survival (OS): 11.8 vs. 13.9 months; HR = 1.009 (95%CI, 0.812–1.254; p  = 0.9336). Safety profile showed a lower rate of grade ≥ 3 hematological treatment-related adverse events (TRAEs) (neutropenia 2.5% vs. 37.1%; thrombocytopenia 2.5% vs. 13.2%) and infections (8.1% vs. 18.7%) for P + LD-DXM, and a higher rate of grade ≥ 1 gastrointestinal TRAEs (52.8% vs. 27.4%), grade ≥ 3 blood creatine phosphokinase (14.3% v s. 0%) and grade ≥ 3 myalgia (5.6% vs. 0%). A second analysis (ECA2) compared POM + LD-DXM with the LD-DXM alone arm included in ADMYRE and showed a treatment effect in OS (HR = 0.762; 95%CI, 0.566–1.026) similar to that observed in ADMYRE (HR = 0.797, 95%CI, 0.596–1.067). Safety profile of POM + LD-DXM was associated to a higher rate of TRAEs, as expected for a combination. In conclusion, P + LD-DXM can be an alternative therapeutic option in r/r MM as this comparison shows that P + LD-DXM is non-inferior in OS to POM + LD-DXM with an advantageous safety profile in terms of hematological and infection events.

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.

The role of the marine environment in the development of anticancer drugs has been widely reviewed, particularly in recent years. However, the innovation in terms of clinical benefits has not been duly emphasized, although there are important breakthroughs associated with the use of marine-derived anticancer agents that have altered the current paradigm in chemotherapy. In addition, the discovery and development of marine drugs has been extremely rewarding with significant scientific gains, such as the discovery of new anticancer mechanisms of action as well as novel molecular targets. Approximately 50 years since the approval of cytarabine, the marine-derived anticancer pharmaceutical pipeline includes four approved drugs and eighteen agents in clinical trials, six of which are in late development. Thus, the dynamic pharmaceutical pipeline consisting of approved and developmental marine-derived anticancer agents offers new hopes and new tools in the treatment of patients afflicted with previously intractable types of cancer.

There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC 50 below 25 µM or 10 2  IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell—type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.

Background: The phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma (r/r MM). ADMYRE met its primary endpoint, showing a 35% reduction in the risk of progression or death. Methods: Results from a pre-planned subgroup of patients aged <75 years are shown here. This subgroup includes most of the patients evaluated in the ADMYRE study: 145/171 patients (84.8%) in the plitidepsin + DXM arm and 71/84 (84.5%) patients in the DXM alone arm. Results: Compared to the overall ADMYRE population, a higher reduction was found with plitidepsin plus DXM for the risk of progression or death in the primary endpoint: 47.7% vs. 35.0% (Hazard ratio [HR] = 0.523 vs. HR = 0.6509). Higher reduction in the risk of death was also found (28.9% vs. 20.3%; HR = 0.711 vs. HR = 0.797), with a clinically meaningful 5-month difference in median overall survival (13.0 months vs. 8.1 months; p = 0.0350). The safety profile of plitidepsin plus DXM in patients aged <75 years was similar to that observed in the overall population of patients treated in the ADMYRE study. The most common adverse events (all grades) related to the study treatment in patients < 75 years were fatigue (39.2% of patients), gastrointestinal (nausea, 39.2%; vomiting, 19.6%; diarrhea, 14.7%), and myalgia (14.0%). Conclusions: Larger differences in efficacy outcomes while maintaining a similar safety profile, together with a novel mechanism of action, suggest that this combination can be a valid option for patients with r/r MM aged <75 years.

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator’s assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.

Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate ( ) and, at present, is manufactured by total synthesis and commercialized as Aplidin . Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.

As per World Health Organization cancer remains as a leading killer disease causing nearly 10 million deaths in 2020. Since the burden of cancer increases worldwide, warranting an urgent search for anti-cancer compounds from natural sources. Secondary metabolites from plants, marine organisms exhibit a novel chemical and structural diversity holding a great promise as therapeutics in cancer treatment. These natural metabolites target only the cancer cells and the normal healthy cells are left unharmed. In the emerging trends of cancer treatment, the natural bioactive compounds have long become a part of cancer chemotherapy. In this review, we have tried to compile about eight bioactive compounds from plant origin viz. combretastatin, ginsenoside, lycopene, quercetin, resveratrol, silymarin, sulforaphane and withaferin A, four marine-derived compounds viz. bryostatins, dolastatins, eribulin, plitidepsin and three microorganisms viz. Clostridium , Mycobacterium bovis and Streptococcus pyogenes with their well-established anticancer potential, mechanism of action and clinical establishments are presented.

The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options. Bioprospection of the marine environment is now a well-settled approach to the discovery and development of anticancer agents that might have their medicinal chemistry developed into clinical candidates. However, despite the massive increase in the number of marine natural products classified as ‘anticancer leads,’ most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy.