Nafamostat for COVID-19

Considering the importance of the 2019 outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in the coronavirus disease 2019 (COVID-19) pandemic, an overview of two proteases that play an important role in the infection by SARS-CoV-2, the main protease of SARS-CoV-2 (MPro) and the host transmembrane protease serine 2 (TMPRSS2), is presented in this review. After summarising the viral replication cycle to identify the relevance of these proteases, the therapeutic agents already approved are presented. Then, this review discusses some of the most recently reported inhibitors first for the viral MPro and next for the host TMPRSS2 explaining the mechanism of action of each protease. Afterward, some computational approaches to design novel MPro and TMPRSS2 inhibitors are presented, also describing the corresponding crystallographic structures reported so far. Finally, a brief discussion on a few reports found some dual-action inhibitors for both proteases is given. This review provides an overview of two proteases of different origins (viral and human host) that have become important targets for the development of antiviral agents to treat COVID-19.

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.

COVID-19 is an infectious disease caused by SARS-CoV-2 leading to the ongoing global pandemic. Infected patients developed a range of respiratory symptoms, including respiratory failure, as well as other extrapulmonary complications. Multiple comorbidities, including hypertension, diabetes, cardiovascular diseases, and chronic kidney diseases, are associated with the severity and increased mortality of COVID-19. SARS-CoV-2 infection also causes a range of cardiovascular complications, including myocarditis, myocardial injury, heart failure, arrhythmias, acute coronary syndrome, and venous thromboembolism. Although a variety of methods have been developed and many clinical trials have been launched for drug repositioning for COVID-19, treatments that consider cardiovascular manifestations and cardiovascular disease comorbidities specifically are limited. In this review, we summarize recent advances in drug repositioning for COVID-19, including experimental drug repositioning, high-throughput drug screening, omics data-based, and network medicine-based computational drug repositioning, with particular attention on those drug treatments that consider cardiovascular manifestations of COVID-19. We discuss prospective opportunities and potential methods for repurposing drugs to treat cardiovascular complications of COVID-19.

This work is a bibliographic review. The search for the necessary information was carried out in the months of November 2022 and January 2023. The databases used were as follows: Pubmed, Academic Google, Scielo, Scopus, and Cochrane library. Results: In total, 101 articles were selected after a review of 486 articles from databases and after applying the inclusion and exclusion criteria. The update on the molecular mechanism of human coronavirus (HCoV) infection was reviewed, describing possible therapeutic targets in the viral response phase. There are different strategies to prevent or hinder the introduction of the viral particle, as well as the replicative mechanism ((protease inhibitors and RNA-dependent RNA polymerase (RdRp)). The second phase of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) involves the activation of hyperinflammatory cascades of the host’s immune system. It is concluded that there are potential therapeutic targets and drugs under study in different proinflammatory pathways such as hydroxychloroquine, JAK inhibitors, interleukin 1 and 6 inhibitors, and interferons.

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.

Abstract: COVID-19, an extremely transmissible and pathogenic viral disease, triggered a global pandemic that claimed lives worldwide. To date, there is no clear and fully effective treatment for COVID-19 disease. Nevertheless, the urgency to discover treatments that can turn the tide has led to the development of a variety of preclinical drugs that are potential candidates for probative results. Although most of these supplementary drugs are constantly being tested in clinical trials against COVID-19, recognized organizations have aimed to outline the prospects in which their use could be considered. A narrative assessment of current articles on COVID-19 disease and its therapeutic regulation was performed. This review outlines the use of various potential treatments against SARS CoV-2, categorized as fusion inhibitors, protease inhibitors, and RNA-dependent RNA polymerase inhibitors, which include antiviral drugs such as Umifenovir, Baricitinib, Camostatmesylate, Nafamostatmesylate, Kaletra, Paxlovide, Darunavir, Atazanavir, Remdesivir, Molnupiravir, Favipiravir, and Ribavirin. To understand the virology of SARS-CoV-2, potential therapeutic approaches for the treatment of COVID-19 disease, synthetic methods of potent drug candidates, and their mechanisms of action have been addressed in this review. It intends to help readers approach the accessible statistics on the helpful treatment strategies for COVID-19 disease and to serve as a valuable resource for future research in this area.

Abstract The ongoing coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to better understand virus–host interactions. We developed a network-based method that expands the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)–host protein interaction network and identifies host targets that modulate viral infection. To disrupt the SARS-CoV-2 interactome, we systematically probed for potent compounds that selectively target the identified host proteins with high expression in cells relevant to COVID-19. We experimentally tested seven chemical inhibitors of the identified host proteins for modulation of SARS-CoV-2 infection in human cells that express ACE2 and TMPRSS2. Inhibition of the epigenetic regulators bromodomain-containing protein 4 (BRD4) and histone deacetylase 2 (HDAC2), along with ubiquitin-specific peptidase (USP10), enhanced SARS-CoV-2 infection. Such proviral effect was observed upon treatment with compounds JQ1, vorinostat, romidepsin and spautin-1, when measured by cytopathic effect and validated by viral RNA assays, suggesting that the host proteins HDAC2, BRD4 and USP10 have antiviral functions. We observed marked differences in antiviral effects across cell lines, which may have consequences for identification of selective modulators of viral infection or potential antiviral therapeutics. While network-based approaches enable systematic identification of host targets and selective compounds that may modulate the SARS-CoV-2 interactome, further developments are warranted to increase their accuracy and cell-context specificity.

Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance.

Abstract The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural proteins (nsp) (e.g. RdRp, Mpro, PLpro, helicase, nsp14, and nsp16), host proteases (e.g. TMPRSS2, cathepsin, and furin) and the pivotal proteins mediating endocytosis (e.g. PIKfyve), as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. Here we present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.