Plitidepsin for COVID-19

Worldwide urbanization and subsequent migration have accelerated the emergence and spread of diverse novel human diseases. Among them, diseases caused by viruses could result in epidemics, typified by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which hit the globe towards the end of December 2019. The global battle against SARS-CoV-2 has reignited interest in finding alternative treatments for viral infections. The marine world offers a large repository of diverse and unique bioactive compounds. Over the years, many antiviral compounds from marine organisms have been isolated and tested in vitro and in vivo. However, given the increasing need for alternative treatment, in silico analysis appears to provide a time- and cost-effective approach to identifying the potential antiviral compounds from the vast pool of natural metabolites isolated from marine organisms. In this perspective review, we discuss marine-derived bioactive metabolites as potential therapeutics for all known disease-causing viruses including the SARS-CoV-2. We demonstrate the efficacy of marine-derived bioactive metabolites in the context of various antiviral activities and their in silico, in vitro, and in vivo capacities.

SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19), has caused more than 179 million infections and 3.8 million deaths worldwide. Throughout the past year, multiple vaccines have already been developed and used, while some others are in the process of being developed. However, the emergence of new mutant strains of SARS-CoV-2 that have demonstrated immune-evading characteristics and an increase in infective capabilities leads to potential ineffectiveness of the vaccines against these variants. The purpose of this review article is to highlight the current understanding of the immunological mechanisms of the virus and vaccines, as well as to investigate some key variants and mutations of the virus driving the current pandemic and their impacts on current management guidelines. We also discussed new technologies being developed for the prevention, treatment, and detection of SARS-CoV-2. In this paper, we thoroughly reviewed and provided crucial information on SARS-CoV-2 virology, vaccines and drugs being used and developed for its prevention and treatment, as well as important variant strains. Our review paper will be beneficial to health care professionals and researchers so they can have a better understanding of the basic sciences, prevention, and clinical treatment of COVID-19 during the pandemic. This paper consists of the most updated information that has been available as of June 21, 2021.

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 IC50 below 25 µM or 102 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.

The rapid spread of the new coronavirus disease (COVID-19) caused by SARS-CoV-2 has become a global pandemic. Although specific vaccines are available and natural drugs are being researched, supportive care and specific treatments to alleviate symptoms and improve patient quality of life remain critical. Chinese medicine (CM) has been employed in China due to the similarities between the epidemiology, genomics, and pathogenesis of SARS-CoV-2 and SARS-CoV. Moreover, the integration of other traditional oriental medical systems into the broader framework of integrative medicine can offer a powerful approach to managing the disease. Additionally, it has been reported that integrated medicine has better effects and does not increase adverse drug reactions in the context of COVID-19. This article examines preventive measures, potential infection mechanisms, and immune responses in Western medicine (WM), as well as the pathophysiology based on principles of complementary medicine (CM). The convergence between WM and CM approaches, such as the importance of maintaining a strong immune system and promoting preventive care measures, is also addressed. Current treatment options, traditional therapies, and classical prescriptions based on empirical knowledge are also explored, with individual patient circumstances taken into account. An analysis of the potential benefits and challenges associated with the integration of complementary and Western medicine (WM) in the treatment of COVID-19 can provide valuable guidance, enrichment, and empowerment for future research endeavors.

Abstract The ongoing COVID-19 pandemic caused by SARS-CoV-2 has raised global concern for public health and the economy. The development of therapeutics and vaccines to combat this virus are continuously progressing. Multi-omics approaches, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, and metallomics, have helped understand the structural and molecular features of the virus, thereby assisting in the design of potential therapeutics and accelerating vaccine development for COVID-19. Here, we provide an up-to-date overview of the latest applications of multi-omics technologies in strategies addressing COVID-19, in order to provide suggestions towards the development of highly effective knowledge-based therapeutics and vaccines.

According to the World Health Organization (WHO), in the second half of 2022, there are about 606 million confirmed cases of COVID-19 and almost 6,500,000 deaths around the world. A pandemic was declared by the WHO in March 2020 when the new coronavirus spread around the world. The short time between the first cases in Wuhan and the declaration of a pandemic initiated the search for ways to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to attempt to cure the disease COVID-19. More than ever, research groups are developing vaccines, drugs, and immunobiological compounds, and they are even trying to repurpose drugs in an increasing number of clinical trials. There are great expectations regarding the vaccine’s effectiveness for the prevention of COVID-19. However, producing sufficient doses of vaccines for the entire population and SARS-CoV-2 variants are challenges for pharmaceutical industries. On the contrary, efforts have been made to create different vaccines with different approaches so that they can be used by the entire population. Here, we summarize about 8162 clinical trials, showing a greater number of drug clinical trials in Europe and the United States and less clinical trials in low-income countries. Promising results about the use of new drugs and drug repositioning, monoclonal antibodies, convalescent plasma, and mesenchymal stem cells to control viral infection/replication or the hyper-inflammatory response to the new coronavirus bring hope to treat the disease.

Viruses with rapid replication and easy mutation can become resistant to antiviral drug treatment. With novel viral infections emerging, such as the recent COVID-19 pandemic, novel antiviral therapies are urgently needed. Antiviral proteins, such as interferon, have been used for treating chronic hepatitis C infections for decades. Natural-origin antimicrobial peptides, such as defensins, have also been identified as possessing antiviral activities, including direct antiviral effects and the ability to induce indirect immune responses to viruses. To promote the development of antiviral drugs, we constructed a data repository of antiviral peptides and proteins (DRAVP). The database provides general information, antiviral activity, structure information, physicochemical information, and literature information for peptides and proteins. Because most of the proteins and peptides lack experimentally determined structures, AlphaFold was used to predict each antiviral peptide’s structure. A free website for users (http://dravp.cpu-bioinfor.org/, accessed on 30 August 2022) was constructed to facilitate data retrieval and sequence analysis. Additionally, all the data can be accessed from the web interface. The DRAVP database aims to be a useful resource for developing antiviral drugs.

This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19.