Simeprevir for COVID-19
Simeprevir has been reported as potentially beneficial for treatment of COVID-19. We have not reviewed these studies. See all other treatments.
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.
Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors, Bioorganic & Medicinal Chemistry, doi:10.1016/j.bmc.2020.115860 ,
In silico studies on therapeutic agents for COVID-19: Drug repurposing approach, Life Sciences, doi:10.1016/j.lfs.2020.117652 ,
Simeprevir potently suppresses SARS-CoV-2 replication and synergizes with remdesivir, bioRxiv, doi:10.1101/2020.05.26.116020 ,
AbstractThe outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp). Our results thus reveal the viral protein targets of simeprevir, and provide preclinical rationale for the combination of simeprevir and remdesivir for the pharmacological management of COVID-19 patients.One Sentence SummaryDiscovery of simeprevir as a potent suppressor of SARS-CoV-2 viral replication that synergizes with remdesivir.
Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2–ACE2 Receptor Interactions, mBio, doi:10.1128/mBio.03681-20 ,
SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases.
Drug repurposing screens identify chemical entities for the development of COVID-19 interventions, Nature Communications, doi:10.1038/s41467-021-23328-0 ,
AbstractThe ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.
After the Hurricane: Anti-COVID-19 Drugs Development, Molecular Mechanisms of Action and Future Perspectives, International Journal of Molecular Sciences, doi:10.3390/ijms25020739 ,
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new coronavirus in the Coronaviridae family. The COVID-19 pandemic, caused by SARS-CoV-2, has undoubtedly been the largest crisis of the twenty-first century, resulting in over 6.8 million deaths and 686 million confirmed cases, creating a global public health issue. Hundreds of notable articles have been published since the onset of this pandemic to justify the cause of viral spread, viable preventive measures, and future therapeutic approaches. As a result, this review was developed to provide a summary of the current anti-COVID-19 drugs, as well as their timeline, molecular mode of action, and efficacy. It also sheds light on potential future treatment options. Several medications, notably hydroxychloroquine and lopinavir/ritonavir, were initially claimed to be effective in the treatment of SARS-CoV-2 but eventually demonstrated inadequate activity, and the Food and Drug Administration (FDA) withdrew hydroxychloroquine. Clinical trials and investigations, on the other hand, have demonstrated the efficacy of remdesivir, convalescent plasma, and monoclonal antibodies, 6-Thioguanine, hepatitis C protease inhibitors, and molnupiravir. Other therapeutics, including inhaled medicines, flavonoids, and aptamers, could pave the way for the creation of novel anti-COVID-19 therapies. As future pandemics are unavoidable, this article urges immediate action and extensive research efforts to develop potent specialized anti-COVID-19 medications.
Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2, RSC Advances, doi:10.1039/d3ra06479d ,
The review outlines coronavirus SARS-CoV-2 morphology, life cycle, and essential proteins, focusing on a design strategy for dual-acting inhibitors for PLpro and Mpro proteases.
Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics, Molecular Aspects of Medicine, doi:10.1016/j.mam.2022.101151 ,
A review on in silico virtual screening methods in COVID-19 using anticancer drugs and other natural/chemical inhibitors, Exploration of Targeted Anti-tumor Therapy, doi:10.37349/etat.2023.00177 ,
The present coronavirus disease 2019 (COVID-19) pandemic scenario has posed a difficulty for cancer treatment. Even under ideal conditions, malignancies like small cell lung cancer (SCLC) are challenging to treat because of their fast development and early metastases. The treatment of these patients must not be jeopardized, and they must be protected as much as possible from the continuous spread of the COVID-19 infection. Initially identified in December 2019 in Wuhan, China, the contagious coronavirus illness 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finding inhibitors against the druggable targets of SARS-CoV-2 has been a significant focus of research efforts across the globe. The primary motivation for using molecular modeling tools against SARS-CoV-2 was to identify candidates for use as therapeutic targets from a pharmacological database. In the published study, scientists used a combination of medication repurposing and virtual drug screening methodologies to target many structures of SARS-CoV-2. This virus plays an essential part in the maturation and replication of other viruses. In addition, the total binding free energy and molecular dynamics (MD) modeling findings showed that the dynamics of various medications and substances were stable; some of them have been tested experimentally against SARS-CoV-2. Different virtual screening (VS) methods have been discussed as potential means by which the evaluated medications that show strong binding to the active site might be repurposed for use against SARS-CoV-2.
Molecular-evaluated and explainable drug repurposing for COVID-19 using ensemble knowledge graph embedding, Scientific Reports, doi:10.1038/s41598-023-30095-z ,
AbstractThe search for an effective drug is still urgent for COVID-19 as no drug with proven clinical efficacy is available. Finding the new purpose of an approved or investigational drug, known as drug repurposing, has become increasingly popular in recent years. We propose here a new drug repurposing approach for COVID-19, based on knowledge graph (KG) embeddings. Our approach learns “ensemble embeddings” of entities and relations in a COVID-19 centric KG, in order to get a better latent representation of the graph elements. Ensemble KG-embeddings are subsequently used in a deep neural network trained for discovering potential drugs for COVID-19. Compared to related works, we retrieve more in-trial drugs among our top-ranked predictions, thus giving greater confidence in our prediction for out-of-trial drugs. For the first time to our knowledge, molecular docking is then used to evaluate the predictions obtained from drug repurposing using KG embedding. We show that Fosinopril is a potential ligand for the SARS-CoV-2 nsp13 target. We also provide explanations of our predictions thanks to rules extracted from the KG and instanciated by KG-derived explanatory paths. Molecular evaluation and explanatory paths bring reliability to our results and constitute new complementary and reusable methods for assessing KG-based drug repurposing.
Paving New Roads Using Allium sativum as a Repurposed Drug and Analyzing its Antiviral Action Using Artificial Intelligence Technology, Iranian Journal of Pharmaceutical Research, doi:10.5812/ijpr-131577 ,
Context: The whole universe is facing a coronavirus catastrophe, and prompt treatment for the health crisis is primarily significant. The primary way to improve health conditions in this battle is to boost our immunity and alter our diet patterns. A common bulb veggie used to flavor cuisine is garlic. Compounds in the plant that are physiologically active are present, contributing to its pharmacological characteristics. Among several food items with nutritional value and immunity improvement, garlic stood predominant and more resourceful natural antibiotic with a broad spectrum of antiviral potency against diverse viruses. However, earlier reports have depicted its efficacy in the treatment of a variety of viral illnesses. Nonetheless, there is no information on its antiviral activities and underlying molecular mechanisms. Objectives: The bioactive compounds in garlic include organosulfur (allicin and alliin) and flavonoid (quercetin) compounds. These compounds have shown immunomodulatory effects and inhibited attachment of coronavirus to the angiotensin-converting enzyme 2 (ACE2) receptor and the Mpro of SARS-CoV-2. Further, we have discussed the contradictory impacts of garlic used as a preventive measure against the novel coronavirus. Method: The GC/MS analysis revealed 18 active chemicals, including 17 organosulfur compounds in garlic. Using the molecular docking technique, we report for the first time the inhibitory effect of the under-consideration compounds on the host receptor ACE2 protein in the human body, providing a crucial foundation for understanding individual compound coronavirus resistance on the main protease protein of SARS-CoV-2. Allyl disulfide and allyl trisulfide, which make up the majority of the compounds in garlic, exhibit the most potent activity. Results: Conventional medicine has proven its efficiency from ancient times. Currently, our article's prime spotlight was on the activity of Allium sativum on the relegation of viral load and further highlighted artificial intelligence technology to study the attachment of the allicin compound to the SARS-CoV-2 receptor to reveal its efficacy. Conclusions: The COVID-19 pandemic has triggered interest among researchers to conduct future research on molecular docking with clinical trials before releasing salutary remedies against the deadly malady.
Repurposing of HIV/HCV protease inhibitors against SARS-CoV-2 3CLpro, Antiviral Research, doi:10.1016/j.antiviral.2022.105419 ,
Virtual Screening of Substances Used in the Treatment of SARS-CoV-2 Infection and Analysis of Compounds With Known Action on Structurally Similar Proteins From Other Viruses, Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113432 ,
Modern drug discovery applications for the identification of novel candidates for COVID-19 infections, Annals of Medicine and Surgery, doi:10.1016/j.amsu.2022.104125 ,
Drug repurposing for identification of potential spike inhibitors for SARS-CoV-2 using molecular docking and molecular dynamics simulations, Methods, doi:10.1016/j.ymeth.2022.02.004 ,
Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2021.104359 ,
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