scholarly journals Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells

2020 ◽  
Author(s):  
Stefano Rensi ◽  
Russ B Altman ◽  
Tianyun Liu ◽  
Yu-Chen Lo ◽  
Greg McInnes ◽  
...  
Keyword(s):  
Serine Protease ◽  
Treatment Options ◽  
Clinical Effects ◽  
The Novel ◽  
Clinical Tool ◽  
Binding Score ◽  
Serine Protease Family ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
High Binding Affinity

The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.

scholarly journals Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells

2020 ◽  
Author(s):  
Stefano Rensi ◽  
Russ B Altman ◽  
Tianyun Liu ◽  
Yu-Chen Lo ◽  
Greg McInnes ◽  
...  
Keyword(s):  
Serine Protease ◽  
Treatment Options ◽  
Clinical Effects ◽  
The Novel ◽  
Clinical Tool ◽  
Binding Score ◽  
Serine Protease Family ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
High Binding Affinity

The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.

COVID 19: Camostat and The Role of Serine Protease Entry Inhibitor TMPRSS2

2020 ◽  
Author(s):  
Stefan Bittmann
Keyword(s):  
Host Cell ◽  
Serine Protease ◽  
Cellular Protein ◽  
Host Cells ◽  
The Novel ◽  
Robert Koch Institute ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

According to the latest research, the novel coronavirus uses the protein angiotensin-converting enzyme 2 (ACE-2) as a receptor for docking to the host cell. Essential for entry is the priming of the spike (S) protein of the virus by host cell proteases. A broadly based team led by infection biologists from the German Primate Centre and with the participation of the Charité Hospital in Berlin, the Hanover Veterinary University Foundation, the BG-UnfallklinikMurnau, the LMU Munich, the Robert Koch Institute and the German Centre for Infection Research wanted to find out how SARS-CoV-2 enters host cells and how this process can be blocked [1]. They have published their findings in the journal "Cell" [1]. The team of scientists was initially able to confirm that SARS-CoV-2 docks to the host cell via the ACE-2 receptor. They also identified Transmembrane serine protease 2 (TMPRSS2) as the cellular protein responsible for entry into the cell [1-3].

scholarly journals Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lukas Wettstein ◽  
Tatjana Weil ◽  
Carina Conzelmann ◽  
Janis A. Müller ◽  
Rüdiger Groß ◽  
...  
Keyword(s):  
Serine Protease ◽  
Immune Defense ◽  
Innate Immune ◽  
Respiratory Pathogen ◽  
The Novel ◽  
Airway Epithelial ◽  
Protein Library ◽  
Epithelial Cultures ◽  
Alpha 1 Antitrypsin ◽  
Novel Coronavirus

AbstractSARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.

TMPRSS4 is a type II transmembrane serine protease involved in cancer and viral infections

2012 ◽  
Vol 393 (9) ◽  
pp. 907-914 ◽  
Author(s):  
Anke Ohler ◽  
Christoph Becker-Pauly
Keyword(s):  
Serine Protease ◽  
Serine Proteases ◽  
Viral Infections ◽  
Proteolytic Enzymes ◽  
Metastatic Potential ◽  
Influenza Viruses ◽  
Type Ii ◽  
Serine Protease Family ◽  
Transmembrane Serine Protease ◽  
Almost All

Abstract Proteolytic enzymes are involved in almost all biological processes reflecting their importance in health and disease. The human genome contains nearly 600 protease-encoding genes forming more than 2% of the total human proteome. The serine proteases, with about 180 members, built the oldest and second largest family of human proteases. Ten years ago, a novel serine protease family named the type II transmembrane family (TTSP) was identified. This minireview summarizes the up-to-date knowledge about the still growing TTSPs, particularly focusing on the pathophysiological functions of the family member type II transmembrane serine protease (TMPRSS) 4. Recent studies provided important data on TMPRSS4 activity associated with the spreading of influenza viruses, mediated by the cleavage of hemagglutinin. Progression and metastatic potential of several cancers is concordant with an increased expression of TMPRSS4, though being a possible diagnostic marker. However, to benefit from TMPRSS4 as a therapeutic target, more data concerning its physiological relevance are needed, as done by a specific morpholino knockdown in zebrafish embryos.

scholarly journals SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far

Pathogens ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 231 ◽  
Author(s):  
Firas A. Rabi ◽  
Mazhar S. Al Zoubi ◽  
Ghena A. Kasasbeh ◽  
Dunia M. Salameh ◽  
Amjad D. Al-Nasser
Keyword(s):  
Vaccine Development ◽  
Current Knowledge ◽  
Treatment Options ◽  
The Novel ◽  
Clinical Criteria ◽  
Health Authorities ◽  
Close Relationship ◽  
Public Health Authorities ◽  
Molecular Information ◽  
Novel Coronavirus

In December 2019, a cluster of fatal pneumonia cases presented in Wuhan, China. They were caused by a previously unknown coronavirus. All patients had been associated with the Wuhan Wholefood market, where seafood and live animals are sold. The virus spread rapidly and public health authorities in China initiated a containment effort. However, by that time, travelers had carried the virus to many countries, sparking memories of the previous coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and causing widespread media attention and panic. Based on clinical criteria and available serological and molecular information, the new disease was called coronavirus disease of 2019 (COVID-19), and the novel coronavirus was called SARS Coronavirus-2 (SARS-CoV-2), emphasizing its close relationship to the 2002 SARS virus (SARS-CoV). The scientific community raced to uncover the origin of the virus, understand the pathogenesis of the disease, develop treatment options, define the risk factors, and work on vaccine development. Here we present a summary of current knowledge regarding the novel coronavirus and the disease it causes.

scholarly journals A Review of Updates on Vaccines and Treatment Options for Covid-19

2021 ◽  
Vol VI (I) ◽  
pp. 1-9
Author(s):  
Naiha Tahir ◽  
Ayema Rehman ◽  
Muhammad Zain ◽  
Mubashir Rehman
Keyword(s):  
Focal Point ◽  
Treatment Options ◽  
The Novel ◽  
Wholesale Market ◽  
Current Management ◽  
Enveloped Virus ◽  
Global Pandemic ◽  
Novel Coronavirus ◽  
In The Beginning ◽  
The City

The novel Coronavirus knew as Covid 19 or SARS-CoV-2, is a newly discovered virus responsible for the huge global pandemic infecting the human race at a deadly pace. This is an RNA enveloped virus that targets the human respiratory system severely while damaging other major systems. Covid 19 pandemic is similar to the severe acute respiratory syndrome related coronavirus (SARS-CoV) endemic and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), but this one is spreading at a fire-speed. The outbreak was known as pneumonia in the beginning; however, it became a threat later on, owing to its high contagion rate. The origin of this virus was sought to be from the seafood wholesale market, very popular in the city of Wuhan. This review has been put together to overview the disease, its etiology, clinical features and treatment methods. The focal point of this review is to highlight the current management of this disease.

scholarly journals Microbes, Clinical trials, Drug Discovery, and Vaccine Development: The Current Perspectives

2021 ◽  
Vol 4 (4) ◽  
pp. 311-323
Author(s):  
Venkataramana Kandi ◽  
Tarun Kumar Suvvari ◽  
Sabitha Vadakedath ◽  
Vikram Godishala
Keyword(s):  
Drug Discovery ◽  
Genetic Variants ◽  
Vaccine Development ◽  
Treatment Options ◽  
Morbidity And Mortality ◽  
Therapeutic Interventions ◽  
Multi Drug Resistance ◽  
The Novel ◽  
Normal Human ◽  
Novel Coronavirus

Because of the frequent emergence of novel microbial species and the re-emergence of genetic variants of hitherto known microbes, the global healthcare system, and human health has been thrown into jeopardy. Also, certain microbes that possess the ability to develop multi-drug resistance (MDR) have limited the treatment options in cases of serious infections, and increased hospital and treatment costs, and associated morbidity and mortality. The recent discovery of the novel Coronavirus (n-CoV), the Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2) that is causing the CoV Disease-19 (COVID-19) has resulted in severe morbidity and mortality throughout the world affecting normal human lives. The major concern with the current pandemic is the non-availability of specific drugs and an incomplete understanding of the pathobiology of the virus. It is therefore important for pharmaceutical establishments to envisage the discovery of therapeutic interventions and potential vaccines against the novel and MDR microbes. Therefore, this review is attempted to update and explore the current perspectives in microbes, clinical research, drug discovery, and vaccine development to effectively combat the emerging novel and re-emerging genetic variants of microbes.

scholarly journals An overview of treatment options for COVID-19

2020 ◽  
Vol 9 (11) ◽  
pp. 1770
Author(s):  
Madhusmita Mohanty Mohapatra ◽  
Manju Rajaram ◽  
Dharm Prakash Dwivedi ◽  
Vishnukant Govindraj ◽  
Pratap Upadhya
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Unknown Origin ◽  
The Novel ◽  
Clinical Trial Registry ◽  
Repurposed Drugs ◽  
Novel Coronavirus ◽  
Meta Analyses ◽  
Effective Drugs

Severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2) which emerged in Wuhan initially as pneumonia of unknown origin in December 2019, later spread to whole world and became pandemic on 11th March, 2020. Many drugs have been proposed but are backed without clinical evidence. Scientific bodies are in the row to discover a reliable vaccine and effective drugs against the novel coronavirus. Many antiviral and anti-parasitic drugs which were thought to have some effect on Coronavirus disease 2019 (COVID-19) have been tried during the crisis but none have shown concrete evidence of action. Randomized clinical trials on the repurposed drugs are now registered under clinical trial registry to look at the safety profile and efficacy of the drugs to be used against SARS-CoV-2. Many meta-analyses are being conducted worldwide to frame evidence for the fight against this novel coronavirus. We are providing below a review of various drugs that have been tried for treatment of COVID-19 as well as different clinical trials which are underway.

scholarly journals Pharmacotherapy for COVID-19: A Ray of Hope

2021 ◽  
Author(s):  
Mayank Kapoor ◽  
Prasan Kumar Panda ◽  
Vivek Mohanty
Keyword(s):  
Large Scale ◽  
Kinase Inhibitors ◽  
Viral Infections ◽  
Treatment Options ◽  
Interferon Alfa ◽  
The Novel ◽  
Plasma Therapy ◽  
Therapeutic Drugs ◽  
Novel Coronavirus ◽  
Multiple Drugs

Most viral infections have limited treatment options available and the same holds for COVID-19, its causative agent being the SARS-CoV-2 virus. Drugs used in the past against Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS) viruses, which belong to the same family of viruses as the novel Coronavirus included ribavirin, interferon (alfa and beta), lopinavir-ritonavir combination, and corticosteroids. There remains controversy regarding their efficacy to date, except for the last one. Hence, large-scale multicentric trials are being conducted involving multiple drugs. Chloroquine and hydroxy-chloroquine were initially taking the race ahead but have now been rejected. Remdesivir was a promising candidate, for which the FDA had issued an emergency use authorization, but now is not recommended by the WHO. Convalescent plasma therapy had promising results in the early severe viremia phase, but the PLACID trial made an obscure end. Only corticosteroids have shown demonstrable benefits in improving mortality rates among severe COVID-19 cases. Many new modalities like monoclonal antibodies and tyrosine kinase inhibitors are discussed. In this chapter, we review the therapeutic drugs under investigation for the COVID-19 treatment, their mode of action, degree of effectiveness, and recommendations by different centers regarding their use in current settings.

scholarly journals Severity of Coronavirus Disease 2019 in Patients with Cancer

2020 ◽  
Vol 4 (2) ◽  
pp. 119-126
Author(s):  
Zahraa Qusairy ◽  
Miran Rada
Keyword(s):  
Global Health ◽  
Treatment Options ◽  
Underlying Disease ◽  
Therapeutic Agents ◽  
The Novel ◽  
Supportive Treatment ◽  
Plasma Therapy ◽  
Patients With Cancer ◽  
Novel Coronavirus

The outbreak of the novel coronavirus disease 2019 (COVID-19) has appeared to be one of the biggest global health threats worldwide with no specific therapeutic agents. As of August 2020, over 22.4 million confirmed cases and more than 788,000 deaths have been reported globally, and the toll is expected to increase before the pandemic is over. Given the aggressive nature of their underlying disease, cancer patients seem to be more vulnerable to COVID-19 and various studies have confirmed this hypothesis. Herein, we review the current information regarding the role of cancer in SARS-CoV-2 infections. Moreover, we discuss the effective supportive treatment options for COVID-19 including Dexamethasone, Tocilizumab and Remdesivir and convalescent plasma therapy (CPT), as well as discuss their efficacy in COVID-19 patients with cancer.

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