Small molecule inhibitors of the SARS-CoV Nsp15 endoribonuclease (original) (raw)
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Novel Inhibitors of SARS-CoV Entry acting by Three Distinct Mechanisms
Journal of Virology, 2013
Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of smallmolecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking of entry of HIV-1 pseudotyped with SARS-CoV surface glyco-
Review of studies on SARS-CoV-2 infection inhibitors
Annals of Agricultural and Environmental Medicine
Introduction and objective. COVID-19 is a human infectious disease manifested by acute respiratory syndrome. On 30 January, 2020, the Word Heath Organization (WHO) declared a COVID-19 pandemic. The purpose of this article is to review publications on the search for substances that show inhibitory activity against SARS-CoV-2 infectivity, paying particular attention to the effect on different stages of the life cycle of the virus. Review methods. The review was based on an analysis of the latest available scientific literature and international databases. The data collected relate to the years 2020-2021. Brief description of the state of knowledge. Extremely intensive research is underway to find compounds that inhibit infection with the SARS-CoV-2 virus. Promising areas of research among the many current endeavours are antiviral compounds that stimulate the immune system, counter proliferation or affect individual viral replication cycles. These include, among others, interferons, monoclonal antibodies, natural compounds, peptides, aptamers, metal salts, and anti-inflammatory agents, inhibitors of viral enzymem, such as the RNA-dependent RNA polymerase. Preparations that help the body to combat the effects of infection have also assumed much importance. Conclusions. The ongoing research is focused on the development of new antiviral agents, as well as the use of the existing drugs on the market. The results of clinical trials are promising and give hope for the development of effective therapies against SARS-CoV-2 and emerging variants of this virus.
Journal of the Chinese Medical Association, 2020
Recently, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was quickly identified as the causal pathogen leading to the outbreak of SARS-like illness all over the world. As the SARS-CoV-2 infection pandemic proceeds, many efforts are being dedicated to the development of diverse treatment strategies. Increasing evidence showed potential therapeutic agents directly acting against SARS-CoV-2 virus, such as interferon, RNA-dependent RNA polymerase inhibitors, protease inhibitors, viral entry blockers, neuraminidase inhibitor, vaccine, antibody agent targeting the SARS-CoV-2 RNA genome, natural killer cells, and nucleocytoplasmic trafficking inhibitor. To date, several direct anti-SARS-CoV-2 agents have demonstrated promising in vitro and clinical efficacy. This article reviews the current and future development of direct acting agents against SARS-CoV-2.
Identification of Potent Drugs and Antiviral Agents for the Treatment of the SARS-CoV-2 Infection
2020
The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of vaccines and the virus-specific drugs has created an opportunity to repurpose existing drugs to examine their efficacy in controlling the virus activities. Here, the inhibition of the RdRp viral protein responsible for the replication of the virus in host cells is examined by evaluating the binding patterns of various approved and investigational antiviral, antibacterial, and anti-cancer drugs by using the molecular docking approach. Some of these drugs have been proposed to be effective against the SARS-Cov-2 virus infection. In an attempt to discover new antiviral agents, artificially expanded genetic alphabets (AEGIS) such as dP, dZ, dJ, dV, dX, dK, dB, dS, dP4, and dZ5 and different sequences of these nucleotides were also docked into the active site of the RdRp protein. It is found that among the various approved and investigational drugs, the Cle...
Small molecules targeting severe acute respiratory syndrome human coronavirus
Proceedings of The National Academy of Sciences, 2004
Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, Ϸ50 compounds were found active at 10 M; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 M. The 50% inhibitory concentrations for the inhibition of viral replication (EC50) and host growth (CC50) were then measured and the selectivity index (SI ؍ CC50͞EC50) was determined. The EC50, based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 M (SI ؍ 7.3), 6.0 M (SI ؍ 2.5), and 0.85 M (SI ؍ 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (Ki ؍ 0.6 M).
Molecules
The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) relies on host cell surface glycans to facilitate interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor. This interaction between ACE2 and the spike protein is a gateway for the virus to enter host cells and may be targeted by antiviral drugs to inhibit viral infection. Therefore, targeting the interaction between these two proteins is an interesting strategy to prevent SARS-CoV-2 infection. A library of glycan mimetics and derivatives was selected for a virtual screening performed against both ACE2 and spike proteins. Subsequently, in vitro assays were performed on eleven of the most promising in silico compounds to evaluate: (i) their efficacy in inhibiting cell infection by SARS-CoV-2 (using the Vero CCL-81 cell line as a model), (ii) their impact on ACE2 expression (in the Vero CCL-81 and MDA-MB-231 cell lines), and (iii) their cytotoxicity in a human lung cell line (A549). We i...
Arab Gulf journal of scientific research, 2022
Purpose: The novel coronavirus disease namely COVID-19 is a viral disease induced by severe acute respiratory syndrome coronavirus (SARS-CoV-2). The cases were first reported in Wuhan, China, by the end of 2019 and subsequently spread worldwide. The virus can be transferred through direct or indirect contact and leads to several manifestations; the most common are fever, dry cough, pneumonia, and acute respiratory distress syndrome (ARDS). COVID-19 has caused massive human and economic losses, posing an ongoing threat. Understanding the current situation and developing a treatment which can be both safe and effective has become essential. In this regard, natural products could be an important resource in the development of treatment for COVID-19, as they have contributed to the treatment of other viruses in the past. This review aims to understand the cellular machinery of SARS-CoV-2 and to identify its drug targets. Methods: Emphasis has been given on the literature survey based on in vitro, in vivo, and in silico studies of natural products as anti-SARS-CoV-2. The important role of these compounds in boosting the immune system was also highlighted. Results: It was found that some natural products showed prominent antiviral activity against coronaviruses through impeding the main machinery used in their pathogenesis and replication cycle. Based on in vitro, in vivo, and in silico investigations, several classes of secondary metabolites, particularly polyphenols, have the ability to disrupt the interaction between SARS-CoV-2 S protein and the ACE2 receptor, resulting in virus entry inhibition. As well as the ability to block the activity of several enzymes involved in the virus replication cycle, including, 3CLpro, PLpro and RdRp. On the other hand, several vitamins and minerals can improve the immune response and are useful for COVID-19 prevention. Essential oils also show the ability to disrupt the fluidity of the virus envelope. Conclusion: Many phytonutrients are counted as bioactive components against SARS-CoV-2, phenolic compounds by their potent mechanisms of action via the immune system rank first. Group B vitamins, vitamins A, C and E as well as minerals such as zinc, selenium and magnesium also play an important role in in preventing the attack by this virus.
Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of smallmolecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking of entry of HIV-1 pseudotyped with SARS-CoV surface glyco-
The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has quickly spread globally, infecting millions and killing hundreds of thousands of people. Herein, to identify potential antiviral agents, 97 natural amide-like compounds known as alkamides and piperamides were tested against SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), and the human angiotensin-converting enzyme 2 (ACE2) using molecular docking and molecular dynamics simulations. The docking results showed that alkamides and dimeric piperamides from Piper species have a high binding affinity and potential antiviral activity against SARS-CoV-2. The absorption, distribution, metabolism, and excretion (ADME) profile and Lipinski's rule of five showed that dimeric piperamides have druglikeness potential. The molecular dynamics results showed that pipercyclobutanamide B forms a complex with Mpro at a similar level of stability than N3-I. Our overall results indicate that alkamides and piperamides, and specifically pipercyclobutanamide B, should be further studied as compounds with SARS-CoV-2 antiviral properties. C oronaviruses are a type of single-stranded positive-sense RNA virus ((+)ssRNA) and are classified in four groups: alpha, beta, delta, and gamma coronaviruses. 1 Three new beta coronaviruses have been identified in the last two decades: the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2003, 2 the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2012, 3 and the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in 2019. 4 SARS-CoV-2 rapidly propagated and was declared a pandemic by the World Health Organization (WHO). MERS-CoV and SARS-CoV induce a mortality rate of 35 and 10% in humans, respectively. 5 The mortality rate by SARS-CoV-2 in humans ranges from 2 to 10%, depending on the country. 6,7 Coronavirus disease (COVID-19) is the infectious disease caused by SARS-CoV-2 and around 1/5 of infected people become seriously ill and have difficult breathing. People with diabetes, heart disease, high blood pressure, and cancer as well as older people are considered high risk. 8 The SARS-CoV and MERS-CoV outbreaks were contained, and the development of vaccines or antiviral drugs for coronaviruses was relegated. 5 As of August 11, 2020, there are more than 20 000 000 confirmed COVID-19 cases and more than 738 000 deaths worldwide. 6 With the magnitude of
2021
Background: The pandemic caused by the novel SARS-CoV-2 virus has escalated rapidly and impacted human health worldwide, in addition to causing severe disruptions to socioeconomic life. There is presently no effective treatment for the disease and this underscores the urgent need for new therapeutic options against this life threatening disease. The traditional strategy for the development of new drugs is a slow and expensive process. Drug repurposing is a valuable alternative strategy that can be used to bypass some of the limitations of traditional drug discovery in order to rapidly develop new therapeutic agents for the management of Covid-19. The present review x-rays recent efforts to re-purpose some antiviral drugs for the treatment Objectives: of SARS-Cov-2 with an emphasis on the structure activity relationships (SAR) of the compounds. A systematic internet Methods: search of three academic databases of published literature was undertaken using relevant keywords and search terms which focused on drug re-purposing against SARS-CoV-2. A total of 853 results were generated and evaluated. The results of the search Results: were screened and relevant articles identified, yielding a total of 83 articles. Some of the drugs identified with potential for repurposing against SARS-CoV-2 include: Arbidol, Favipiravir, Ribavirin, Nitazoxanide etc. It is hoped that the Conclusion: information generated in this review will help deepen understanding of the potential mechanism of anti-SARS-CoV-2 action of the compounds and also draw attention to opportunities that exist for structural modification of these molecules with the aim of improving and enhancing their selectivity and efficacy against SARS-CoV-2.