Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug

In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2.

Download Full-text

SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome

Molecules ◽

10.3390/molecules26051409 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1409

Author(s):

Anna Maria Sardanelli ◽

Camilla Isgrò ◽

Luigi Leonardo Palese

Keyword(s):

Active Site ◽

Therapeutic Strategy ◽

Silybum Marianum ◽

Antiviral Therapies ◽

Global Pandemic ◽

Main Protease ◽

Toxicological Profile ◽

Starting Point ◽

Antiviral Activities

In late 2019, a global pandemic occurred. The causative agent was identified as a member of the Coronaviridae family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we present an analysis on the substances identified in the human metabolome capable of binding the active site of the SARS-CoV-2 main protease (Mpro). The substances present in the human metabolome have both endogenous and exogenous origins. The aim of this research was to find molecules whose biochemical and toxicological profile was known that could be the starting point for the development of antiviral therapies. Our analysis revealed numerous metabolites—including xenobiotics—that bind this protease, which are essential to the lifecycle of the virus. Among these substances, silybin, a flavolignan compound and the main active component of silymarin, is particularly noteworthy. Silymarin is a standardized extract of milk thistle, Silybum marianum, and has been shown to exhibit antioxidant, hepatoprotective, antineoplastic, and antiviral activities. Our results—obtained in silico and in vitro—prove that silybin and silymarin, respectively, are able to inhibit Mpro, representing a possible food-derived natural compound that is useful as a therapeutic strategy against COVID-19.

Download Full-text

Patent Insight into the Development of Therapeutic Strategies against Coronaviruses

The Open COVID Journal ◽

10.2174/2666958702101010093 ◽

2021 ◽

Vol 1 (1) ◽

pp. 93-100

Author(s):

Hai-Long Zhang ◽

Ai-Feng Zhou ◽

Yiqian Li

Keyword(s):

Therapeutic Strategy ◽

Vaccine Development ◽

Rna Viruses ◽

Therapeutic Strategies ◽

Peptide Drugs ◽

Leading Role ◽

Global Pandemic ◽

Effective Therapeutic Strategy ◽

Insight Into ◽

Development And Evolution

Coronaviruses are a group of RNA viruses, which cause diseases in humans. The emergence of COVID-19, has caused a global pandemic. It is focused on developing an effective therapeutic strategy against COVID-19. To better understand the development and evolution of therapeutic strategies against coronaviruses, we conducted US granted patents analysis. The results showed vaccines played a leading role in therapies against coronaviruses. Both attenuated vaccines and recombinant genetic vaccines were very important approaches in vaccine development against coronaviruses. It is not a rapid approach to develop peptide drugs against COVID-19 or future novel coronaviruses. The study was the first one to show the development and evolution in therapeutic strategies against coronaviruses based on patent insight. The present study provides a new insight into the development of therapeutic strategies against coronaviruses.

Download Full-text

A review on the SARS-CoV-2 mediated global pandemic: proximal origin, pathogenicity and therapeutic approaches

10.31219/osf.io/fpqsw ◽

2020 ◽

Author(s):

Soumi Chatterjee ◽

Bikram Dhara ◽

Dattatreya Mukherjee ◽

Arup Kumar Mitra

Keyword(s):

Vaccine Development ◽

Geographical Area ◽

Antiviral Drug ◽

Drug Repurposing ◽

The Novel ◽

Therapeutic Approaches ◽

Health Crisis ◽

Public Health Crisis ◽

Global Pandemic ◽

Viral Outbreak

The world is amidst a public health crisis as the pandemic has shook us to the core. The COVID-19 caused by the novel SARS-CoV-2 is of zoonotic origin and this tries to explain what could have been the possible proximal origins for the disease in humans. Our review aims at addressing the question like what structural or genomic vicissitude enabled the viral outbreak across genera and so efficiently infect the human populace across the globe. We also try to discuss the prospect of drug repurposing and scope for vaccine development considering the rapid genome modification of the virus. Another finding lies into the action of pre-existing drugs when they are applied in combination and probably that shades some light on the therapeutic approaches. Several investigation have been performed but we are still in search of a novel antiviral drug. With that vision, our focus shifted on the evaluation of existing drugs with positive response against the novel corona virus. We also try discussing certain trends including increased immunity to the disease in the population from a particular geographical area.

Download Full-text

Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

10.26434/chemrxiv.12118857.v1 ◽

2020 ◽

Author(s):

Mahmudul Hasan ◽

Md Sorwer Alam Parvez ◽

Kazi Faizul Azim ◽

Abdus Shukur Imran ◽

Topu Raihan ◽

...

Keyword(s):

Molecular Docking ◽

Drug Repurposing ◽

Pharmacokinetic Parameters ◽

The Novel ◽

Drug Candidates ◽

Target Drug ◽

Global Pandemic ◽

Main Protease ◽

Docking Approach ◽

Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

Download Full-text

Xanthohumol Is a Potent Pan-Inhibitor of Coronaviruses Targeting Main Protease

International Journal of Molecular Sciences ◽

10.3390/ijms222212134 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12134

Author(s):

Yuxi Lin ◽

Ruochen Zang ◽

Yanlong Ma ◽

Zhuoya Wang ◽

Li Li ◽

...

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Small Molecule ◽

Drug Target ◽

Antiviral Drug ◽

High Morbidity ◽

Lead Compound ◽

Human Beings ◽

Main Protease ◽

Ic50 Value

Coronaviruses cause diseases in humans and livestock. The SARS-CoV-2 is infecting millions of human beings, with high morbidity and mortality worldwide. The main protease (Mpro) of coronavirus plays a pivotal role in viral replication and transcription, which, in theory, is an attractive drug target for antiviral drug development. It has been extensively discussed whether Xanthohumol is able to help COVID-19 patients. Here, we report that Xanthohumol, a small molecule in clinical trials from hops (Humulus lupulus), was a potent pan-inhibitor for various coronaviruses by targeting Mpro, for example, betacoronavirus SARS-CoV-2 (IC50 value of 1.53 μM), and alphacoronavirus PEDV (IC50 value of 7.51 μM). Xanthohumol inhibited Mpro activities in the enzymatical assays, while pretreatment with Xanthohumol restricted the SARS-CoV-2 and PEDV replication in Vero-E6 cells. Therefore, Xanthohumol is a potent pan-inhibitor of coronaviruses and an excellent lead compound for further drug development.

Download Full-text

Coronavirus Disease 2019 (COVID-19): Origin, Impact, and Drug Development

10.5772/intechopen.98358 ◽

2021 ◽

Author(s):

Amaresh Mishra ◽

Nisha Nair ◽

Amit K. Yadav ◽

Pratima Solanki ◽

Jaseela Majeed ◽

...

Keyword(s):

Vaccine Development ◽

Therapeutic Option ◽

Treatment Strategies ◽

Drug Repurposing ◽

Cost Effective ◽

High Sequence Identity ◽

Drug Candidates ◽

Global Pandemic ◽

The People ◽

Health Organization

At the end of December 2019, in Wuhan, China, a rapidly spreading unknown virus was reported to have caused coronavirus disease of 2019 (COVID-19). Origin linked to Wuhan’s wholesale food market where live animals are sold. This disease is caused by SARS Coronavirus-2 (SARS-CoV-2), which is closely related to the Severe Acute Respiratory Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). This virus shares a high sequence identity with bat-derived SARS-like Coronavirus, which indicating its zoonotic origin. The virus spread globally, provoking widespread attention and panic. This Coronavirus is highly pathogenic and causes mild to severe respiratory disorders. Later, it was declared a global pandemic by the World Health Organization (WHO) due to its highly infectious nature and worldwide mortality rate. This virus is a single-stranded, positive-sense RNA genome, and its genome length about 26 to 32 kb that infects a broad range of vertebrates. The researchers worldwide focus on establishing treatment strategies on drug and vaccine development to prevent this COVID-19 pandemic. A drug repurposing approach has been used to identify a rapid treatment for the people affected by COVID-19, which could be cost-effective and bypass some Food and Drug Association (FDA) regulations to move quickly in phase-3 trials. However, there is no promising therapeutic option available yet. This book chapter addresses current information about the COVID-19 disease, including its origins, impacts, and the novel potential drug candidates that can help treat the COVID-19.

Download Full-text

Diverse Effects of Exosomes on COVID-19: A Perspective of Progress From Transmission to Therapeutic Developments

Frontiers in Immunology ◽

10.3389/fimmu.2021.716407 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sangiliyandi Gurunathan ◽

Min Hee Kang ◽

Jin-Hoi Kim

Keyword(s):

Vaccine Development ◽

Antiviral Drug ◽

Treatment Strategies ◽

Antiviral Drugs ◽

Therapeutic Benefits ◽

Global Pandemic ◽

Lung Injuries ◽

Infected Cells ◽

Intercellular Spread

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus and the causative agent of the current global pandemic of coronavirus disease 2019 (COVID-19). There are currently no FDA-approved antiviral drugs for COVID-19 and there is an urgent need to develop treatment strategies that can effectively suppress SARS-CoV-2 infection. Numerous approaches have been researched so far, with one of them being the emerging exosome-based therapies. Exosomes are nano-sized, lipid bilayer-enclosed structures, share structural similarities with viruses secreted from all types of cells, including those lining the respiratory tract. Importantly, the interplay between exosomes and viruses could be potentially exploited for antiviral drug and vaccine development. Exosomes are produced by virus-infected cells and play crucial roles in mediating communication between infected and uninfected cells. SARS-CoV-2 modulates the production and composition of exosomes, and can exploit exosome formation, secretion, and release pathways to promote infection, transmission, and intercellular spread. Exosomes have been exploited for therapeutic benefits in patients afflicted with various diseases including COVID-19. Furthermore, the administration of exosomes loaded with immunomodulatory cargo in combination with antiviral drugs represents a novel intervention for the treatment of diseases such as COVID-19. In particular, exosomes derived from mesenchymal stem cells (MSCs) are used as cell-free therapeutic agents. Mesenchymal stem cell derived exosomes reduces the cytokine storm and reverse the inhibition of host anti-viral defenses associated with COVID-19 and also enhances mitochondrial function repair lung injuries. We discuss the role of exosomes in relation to transmission, infection, diagnosis, treatment, therapeutics, drug delivery, and vaccines, and present some future perspectives regarding their use for combating COVID-19.

Download Full-text

Peptide Derivatives of the Zonulin Inhibitor Larazotide (AT1001) as Potential Anti SARS CoV-2: Molecular Modelling, Synthesis and Bioactivity Evaluation

International Journal of Molecular Sciences ◽

10.3390/ijms22179427 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9427

Author(s):

Simone Di Micco ◽

Simona Musella ◽

Marina Sala ◽

Maria C. Scala ◽

Graciela Andrei ◽

...

Keyword(s):

Catalytic Domain ◽

Antiviral Agents ◽

Antiviral Drug ◽

Drug Repurposing ◽

Fast Response ◽

Main Protease ◽

Promising Target ◽

Peptide Derivatives ◽

Novel Coronavirus ◽

Derivatives Of

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (Mpro), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds Mpro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.

Download Full-text

Coronavirus Disease 2019: Virology and Drug Targets

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666201209145302 ◽

2020 ◽

Vol 20 ◽

Author(s):

Praveen Thaggikuppe Krishnamurthy

Keyword(s):

High Throughput Screening ◽

Drug Targets ◽

Vaccine Development ◽

Antiviral Drug ◽

Drug Repurposing ◽

Structural Proteins ◽

Current Status ◽

Approved Drugs ◽

Viral Target ◽

Fda Approved Drugs

: The Coronavirus Disease 2019, a pandemic caused by novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is seriously affecting global health and the economy. As the vaccine development takes time, the current research is focused on repurposing FDA approved drugs against the viral target proteins. This review discusses the current understanding of SARS-CoV-2 virology, its target structural proteins (S- glycoprotein), non-structural proteins (3- chymotrypsin-like protease, papain-like protease, RNA-dependent RNA polymerase, and helicase) and accessory proteins, drug discovery strategies (drug repurposing, artificial intelligence, and high-throughput screening), and the current status of antiviral drug development.

Download Full-text

Flavonoid compounds of buah merah (Pandanus conoideus Lamk) as a potent SARS-CoV-2 main protease inhibitor: in silico approach

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00309-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Abd. Kakhar Umar

Keyword(s):

Protein Interactions ◽

In Silico ◽

Antiviral Drug ◽

Pharmacokinetic Profile ◽

Unbound Fraction ◽

Receptor Complexes ◽

Flavonoid Compounds ◽

Global Pandemic ◽

Main Protease ◽

Low Toxicity

Abstract Background COVID19 is a global pandemic that threatens all nations. As there is no effective antiviral drug for COVID19, we examined the potency of natural ingredients against the SARS-CoV-2 main protease (PDB ID 6YNQ). Buah merah is a typical fruit from Papua, Indonesia, which is known to contain high levels of carotenoids and flavonoids. The contents have been proven to be effective as antiparasitic and anti-HIV. An in silico approach to 16 metabolites of buah merah (Pandanus conoideus Lamk) was carried out using AutoDock Vina. Furthermore, the study of the dynamics of ligand–protein interactions was carried out using CABS Flex 2.0 server to determine the test ligand and receptor complexes' stability. ADMET prediction was also carried out to study the pharmacokinetic profile of potential antiviral candidates. Result The docking results showed that 3 of the 16 buah merah metabolites were potent inhibitors against the SARS-CoV-2 main protease. The flavonoid compounds are quercetin 3′-glucoside, quercetin 3-O-glucose, and taxifolin 3-O-α-arabinopyranose with a binding affinity of − 9.7, − 9.3, and − 8.8, respectively, with stable ligand–protein complex. ADMET study shows that the three compounds are easily dissolved, easily absorbed orally and topically, have a high unbound fraction, low toxicity, and non-irritant. Conclusion We conclude that quercetin 3′-glucoside, quercetin 3-O-glucose, and taxifolin 3-O-α-arabinopyranose can be used and improved as potential anti-SARS-CoV-2 agents in further study.

Download Full-text