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Ebselen for COVID-19

Ebselen has been reported as potentially beneficial for treatment of COVID-19. We have not reviewed these studies. See all other treatments.
Sharun et al., A comprehensive review on pharmacologic agents, immunotherapies and supportive therapeutics for COVID-19, Narra J, doi:10.52225/narra.v2i3.92
The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.
Yarovaya et al., The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses, Viruses, doi:10.3390/v16020215
Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle—just as pure (+)- and (−)-usnic acids—showed no anti-3CLpro activity. Kinetic parameters of the most active compound, (+)-3e, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand–protein complex. Active compound (+)-3e was found to bind with minimum free energy; the binding of inactive compound (+)-3g is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, (+)-3e demonstrated pronounced antiviral activity against all the strains.
Katre et al., Review on development of potential inhibitors of SARS-CoV-2 main protease (MPro), Future Journal of Pharmaceutical Sciences, doi:10.1186/s43094-022-00423-7
Abstract Background The etiological agent for the coronavirus illness outbreak in 2019–2020 is a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19), whereas coronavirus disease pandemic of 2019 (COVID-19) has compelled the implementation of novel therapeutic options. Main body of the abstract There are currently no targeted therapeutic medicines for this condition, and effective treatment options are quite restricted; however, new therapeutic candidates targeting the viral replication cycle are being investigated. The primary protease of the severe acute respiratory syndrome coronavirus 2 virus is a major target for therapeutic development (MPro). Severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus (MERS-CoV) all seem to have a structurally conserved substrate-binding domain that can be used to develop novel protease inhibitors. Short conclusion With the recent publication of the X-ray crystal structure of the severe acute respiratory syndrome coronavirus 2 Mm, virtual and in vitro screening investigations to find MPro inhibitors are fast progressing. The focus of this review is on recent advancements in the quest for small-molecule inhibitors of the severe acute respiratory syndrome coronavirus 2 main protease.
Calleja et al., Inhibitors of SARS-CoV-2 PLpro, Frontiers in Chemistry, doi:10.3389/fchem.2022.876212
The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.
Kuo et al., Kinetic Characterization and Inhibitor Screening for the Proteases Leading to Identification of Drugs against SARS-CoV-2, Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.02577-20
Coronavirus (CoV) disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has claimed many lives worldwide and is still spreading since December 2019. The 3C-like protease (3CL pro ) and papain-like protease (PL pro ) are essential for maturation of viral polyproteins in SARS-CoV-2 life cycle and thus regarded as key drug targets for the disease.
Brown et al., High-Throughput Screening for Inhibitors of the SARS-CoV-2 Protease Using a FRET-Biosensor, Molecules, doi:10.3390/molecules25204666
The global SARS-CoV-2 pandemic started late 2019 and currently continues unabated. The lag-time for developing vaccines means it is of paramount importance to be able to quickly develop and repurpose therapeutic drugs. Protein-based biosensors allow screening to be performed using routine molecular laboratory equipment without a need for expensive chemical reagents. Here we present a biosensor for the 3-chymotrypsin-like cysteine protease from SARS-CoV-2, comprising a FRET-capable pair of fluorescent proteins held in proximity by a protease cleavable linker. We demonstrate the utility of this biosensor for inhibitor discovery by screening 1280 compounds from the Library of Pharmaceutically Active Compounds collection. The screening identified 65 inhibitors, with the 20 most active exhibiting sub-micromolar inhibition of 3CLpro in follow-up EC50 assays. The top hits included several compounds not previously identified as 3CLpro inhibitors, in particular five members of a family of aporphine alkaloids that offer promise as new antiviral drug leads.
Yuan et al., The role of cell death in SARS-CoV-2 infection, Signal Transduction and Targeted Therapy, doi:10.1038/s41392-023-01580-8
AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), showing high infectiousness, resulted in an ongoing pandemic termed coronavirus disease 2019 (COVID-19). COVID-19 cases often experience acute respiratory distress syndrome, which has caused millions of deaths. Apart from triggering inflammatory and immune responses, many viral infections can cause programmed cell death in infected cells. Cell death mechanisms have a vital role in maintaining a suitable environment to achieve normal cell functionality. Nonetheless, these processes are dysregulated, potentially contributing to disease pathogenesis. Over the past decades, multiple cell death pathways are becoming better understood. Growing evidence suggests that the induction of cell death by the coronavirus may significantly contributes to viral infection and pathogenicity. However, the interaction of SARS-CoV-2 with cell death, together with its associated mechanisms, is yet to be elucidated. In this review, we summarize the existing evidence concerning the molecular modulation of cell death in SARS-CoV-2 infection as well as viral-host interactions, which may shed new light on antiviral therapy against SARS-CoV-2.
Tam et al., Targeting SARS-CoV-2 Non-Structural Proteins, International Journal of Molecular Sciences, doi:10.3390/ijms241613002
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped respiratory β coronavirus that causes coronavirus disease (COVID-19), leading to a deadly pandemic that has claimed millions of lives worldwide. Like other coronaviruses, the SARS-CoV-2 genome also codes for non-structural proteins (NSPs). These NSPs are found within open reading frame 1a (ORF1a) and open reading frame 1ab (ORF1ab) of the SARS-CoV-2 genome and encode NSP1 to NSP11 and NSP12 to NSP16, respectively. This study aimed to collect the available literature regarding NSP inhibitors. In addition, we searched the natural product database looking for similar structures. The results showed that similar structures could be tested as potential inhibitors of the NSPs.
Yadav et al., Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19, Cells, doi:10.3390/cells10040821
Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.
Mushebenge et al., Assessing the Potential Contribution of in Silico Studies in Discovering Drug Candidates that Interact with Various SARS-CoV-2 Receptors, MDPI AG, doi:10.20944/preprints202308.0434.v1
COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, and AP2-associated protein kinase 1. In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of drug candidates to target receptors, providing insight into their potential efficacy. However, it is crucial to consider both the advantages and limitations of these studies and to complement them with experimental validation to ensure the efficacy and safety of identified drug candidates.
Carabineiro et al., CuFe2O4 Magnetic Nanoparticles as Heterogeneous Catalysts for Synthesis of Dihydropyrimidinones as Inhibitors of SARS-CoV-2 Surface Proteins—Insights from Molecular Docking Studies, Processes, doi:10.3390/pr11082294
In this study, we present the highly efficient and rapid synthesis of substituted dihydropyrimidinone derivatives through an ultrasound-accelerated approach. We utilize copper ferrite (CuFe2O4) magnetic nanoparticles as heterogeneous catalysts, employing the well-known Biginelli reaction, under solvent-free conditions. The impact of the solvent, catalyst amount, and catalyst type on the reaction performance is thoroughly investigated. Our method offers several notable advantages, including facile catalyst separation, catalyst reusability for up to three cycles with the minimal loss of activity, a straightforward procedure, mild reaction conditions, and impressive yields, ranging from 79% to 95%, within short reaction times of 20 to 40 min. Furthermore, in the context of fighting COVID-19, we explore the potential of substituted dihydropyrimidinone derivatives as inhibitors of three crucial SARS-CoV-2 proteins. These proteins, glycoproteins, and proteases play pivotal roles in the entry, replication, and spread of the virus. Peptides and antiviral drugs targeting these proteins hold great promise in the development of effective treatments. Through theoretical molecular docking studies, we compare the binding properties of the synthesized dihydropyrimidinone derivatives with the widely used hydroxychloroquine molecule as a reference. Our findings reveal that some of the tested molecules exhibit superior binding characteristics compared to hydroxychloroquine, while others demonstrate comparable results. These results highlight the potential of our synthesized derivatives as effective inhibitors in the fight against SARS-CoV-2.
Zmudzinski et al., Ebselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins: PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase, Scientific Reports, doi:10.1038/s41598-023-35907-w
AbstractProteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage—a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and antiviral assays. In this study, we screened a collection of 34 ebselen and ebselen diselenide derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Independently, ebselen was shown to inhibit the N7-methyltransferase activity of SARS-CoV-2 nsp14 protein involved in viral RNA cap modification. Hence, selected compounds were also evaluated as nsp14 inhibitors. In the second part of our work, we employed 11 ebselen analogues—bis(2-carbamoylaryl)phenyl diselenides—in biological assays to evaluate their anti-SARS-CoV-2 activity in Vero E6 cells. We present their antiviral and cytoprotective activity and also low cytotoxicity. Our work shows that ebselen, its derivatives, and diselenide analogues constitute a promising platform for development of new antivirals targeting the SARS-CoV-2 virus.
Farkaš et al., A Tale of Two Proteases: MPro and TMPRSS2 as Targets for COVID-19 Therapies, Pharmaceuticals, doi:10.3390/ph16060834
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.
Oliver et al., Different drug approaches to COVID-19 treatment worldwide: an update of new drugs and drugs repositioning to fight against the novel coronavirus, Therapeutic Advances in Vaccines and Immunotherapy, doi:10.1177/25151355221144845
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.
Graf et al., Ferrocenoyl-substituted quinolinone and coumarin as organometallic inhibitors of SARS-CoV-2 3CLpro main protease, Metallomics, doi:10.1093/mtomcs/mfad023
Abstract The 3-chymotrypsin-like protease 3CLpro from SARS-CoV-2 is a potential target for antiviral drug development. In this work, three organometallic ferrocene-modified quinolinones and coumarins were compared to their benzoic acid ester analogues with regard to inhibition of 3CLpro using a HPLC-based assay with a 15mer model peptide as the substrate. In contrast to FRET-based assays, this allows direct identification of interference of buffer constituents with the inhibitors, as demonstrated by the complete abolishment of ebselen inhibitory activity in the presence of DTT as a redox protectant. The presence of the organometallic ferrocene moiety significantly increased the stability of the title compounds towards hydrolysis. Among the studied compounds, 4-ferrocenyloxy-1-methyl-quinol-2-one was identified as the most stable and potent inhibitor candidate. IC50 values determined for ebselen and this sandwich complex compound are (0.40 ± 0.07) and (2.32 ± 0.21) μM, respectively.
Rudramurthy et al., In-Vitro Screening of Repurposed Drug Library against Severe Acute Respiratory Syndrome Coronavirus-2, Medical Research Archives, doi:10.18103/mra.v11i2.3595
The current pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) demands rapid identification of new antiviral molecules from the existing drugs. Drug repurposing is a significant alternative for pandemics and emerging diseases because of the availability of preclinical data, documented safety in clinic and possibility of immediate production and scalable capacity and supply. Several drugs such as ivermectin and hydroxy chloroquine have been repurposed as anti-SARS-CoV-2 agents, but the effect of these compounds in treating the COVID-19 patients remains sub-optimal. In the present study repurposed drug libraries consisting of 560 compounds from two different sources have been screened against SARS-CoV-2 isolate USA-WA1/2020 in Vero-E6 cell line and 24 compounds were found active. The SARS-CoV-2 virus propagated in Vero E6 cell line and used in screening the drug libraries was sequenced by Next Generation Sequencing to identify any mutations that may have accumulated in the virus genome. The whole genome sequencing data of SARS-CoV-2 showed 9 and 6 single nucleotide polymorphisms in spike protein with reference to Wuhan-Hu-1(NC045512.2) and USA/WA-CDC-WA1/2020 (MN985325.1) isolates respectively. The present study identified 24 compounds active against SARS-CoV-2 isolate USA-WA1/2020 out of 560 repurposed drugs from two libraries. The IC-50 values of the identified hits range from 0.4 µM to 16 µM. Further studies on the repurposed drugs identified in the present screen may be helpful in the rapid development of antiviral drugs against SARS-CoV-2.
Zhong et al., Recent advances in small-molecular therapeutics for COVID-19, Precision Clinical Medicine, doi:10.1093/pcmedi/pbac024
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.
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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