scholarly journals Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease

2021 ◽  
Vol 478 (13) ◽  
pp. 2517-2531
Author(s):  
Chew Theng Lim ◽  
Kang Wei Tan ◽  
Mary Wu ◽  
Rachel Ulferts ◽  
Lee A. Armstrong ◽  
...  
Keyword(s):  
Small Molecule ◽  
Antiviral Agents ◽  
Expression And Purification ◽  
Protein Conjugates ◽  
Antiviral Compounds ◽  
Life Threatening ◽  
Polyprotein Precursor ◽  
Novel Coronavirus ◽  
Protease Assay

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.

scholarly journals Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp3 Papain-like Protease

2021 ◽  
Author(s):  
Lee A Armstrong ◽  
Rupert Beale ◽  
Ganka Bineva-Todd ◽  
Berta Canal ◽  
John FX Diffley ◽  
...  
Keyword(s):  
Small Molecule ◽  
Antiviral Agents ◽  
Chemical Library ◽  
Protein Conjugates ◽  
Antiviral Compounds ◽  
Life Threatening ◽  
Polyprotein Precursor ◽  
Novel Coronavirus ◽  
Protease Assay

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom chemical library from which we identified Dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.

SARS-COV2 virus and Coronavirus disease (COVID-19)

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 977-982
Author(s):  
Mohamed J. Saadh ◽  
Bashar Haj Rashid M ◽  
Roa’a Matar ◽  
Sajeda Riyad Aldibs ◽  
Hala Sbaih ◽  
...  
Keyword(s):  
Close Contact ◽  
Antiviral Agents ◽  
Health Concern ◽  
The Novel ◽  
Global Public Health ◽  
Fatal Disease ◽  
Mild Disease ◽  
Life Threatening ◽  
Novel Coronavirus

SARS-COV2 virus causes Coronavirus disease (COVID-19) and represents the causative agent of a potentially fatal disease that is of great global public health concern. The novel coronavirus (2019) was discovered in 2019 in Wuhan, the market of the wet animal, China with viral pneumonia cases and is life-threatening. Today, WHO announces COVID-19 outbreak as a pandemic. COVID-19 is likely to be zoonotic. It is transmitted from bats as intermediary animals to human. Also, the virus is transmitted from human to human who is in close contact with others. The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is nearly supportive; the role of antiviral agents is yet to be established. The SARS-COV2 virus spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. In this article, we aimed to summarize the transmission, symptoms, pathogenesis, diagnosis, treatment, and vaccine to control the spread of this fatal disease.

scholarly journals From Wuhan to COVID-19 Pandemic: An Up-to-Date Review of Its Pathogenesis, Potential Therapeutics, and Recent Advances

2020 ◽  
Vol 8 (6) ◽  
pp. 850 ◽  
Author(s):  
Ikrame Zeouk ◽  
Khadija Bekhti ◽  
Jacob Lorenzo-Morales
Keyword(s):  
Antiviral Agents ◽  
Pathogen Inactivation ◽  
Life Threatening ◽  
Antiparasitic Drugs ◽  
Asymptomatic Individuals ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Tract Infections ◽  
Fda Approved Drugs ◽  
Screening Approaches

The emergence of a novel human coronavirus (SARS-CoV-2) causing severe contagious respiratory tract infections presents a serious threat to public health worldwide. To date, there are no specific antiviral agents available for this disease, currently known as COVID-19. Therefore, genomic sequencing and therapeutic clinical trials are being conducted to develop effective antiviral agents. Several reports have investigated FDA-approved drugs as well as in silico virtual screening approaches such as molecular docking and modeling to find novel antiviral agents. Until now, antiparasitic drugs such as chloroquine have shown the most relevant results. Furthermore, there is an urgent need to understand the pathogenesis of this novel coronavirus, its transmission routes, surface survival and evolution in the environment. So far, the scientific community has indicated a possible transmission of COVID-19 via blood transfusion which is challenging in the case of asymptomatic individuals. Protocols for pathogen inactivation are also needed. In this paper, we reviewed recent findings about this life-threatening pandemic.

scholarly journals Disequilibrium and COVID-19: Effectively Applying Crisis Intervention

2020 ◽  
Author(s):  
Stephen Oby
Keyword(s):  
Suicidal Ideation ◽  
Crisis Intervention ◽  
Physical Violence ◽  
The Novel ◽  
Coping Capacity ◽  
Sudden Loss ◽  
Social Work Values ◽  
Life Threatening ◽  
Novel Coronavirus

Crisis intervention is widely understood as a response to life-threatening emergencies and therefore often limited in its application to natural disasters, severe physical violence, suicidal ideation, and similarly dangerous incidents. While crisis intervention is appropriate for these scenarios, historical definitions of crisis suggest the term and related interventions have much broader application. The ramifications of the novel coronavirus and related cultural fallout increase vulnerability and impair coping capacity in such a way that individuals are significantly more likely to enter crisis states, demanding a prompt reconsideration of the breadth of this practice technique. Successful application of crisis intervention reduces the long-term psychological implications for individuals encountering sudden loss, unexpected traumas, and other hazards that overwhelm traditional coping strategies, outcomes all made more likely by this pandemic. Crisis intervention is a structured, time-limited, problem-oriented treatment modality that is well suited to a remote practice environment because it is directive in its approach and requires few contacts at a time when client access is potentially limited. This paper examines the course of crisis with or without intervention, assessment and intervention tactics, social work values when applying crisis intervention, and the implications of the use of this modality as it relates to COVID-19.

scholarly journals An Evaluation of Traditional Persian Medicine for the Management of SARS-CoV-2

2020 ◽  
Vol 11 ◽  
Author(s):  
Roodabeh Bahramsoltani ◽  
Roja Rahimi
Keyword(s):  
Medicinal Plants ◽  
Clinical Studies ◽  
Antiviral Agents ◽  
Molecular Structures ◽  
Antiviral Compounds ◽  
Pharmacological Studies ◽  
Persian Medicine ◽  
Life Threatening ◽  
Traditional Persian Medicine ◽  
Therapeutic Activities

A new coronavirus causing severe acute respiratory syndrome (SARS-CoV-2) has emerged and with it, a global investigation of new antiviral treatments and supportive care for organ failure due to this life-threatening viral infection. Traditional Persian Medicine (TPM) is one of the most ancient medical doctrines mostly known with the manuscripts of Avicenna and Rhazes. In this paper, we first introduce a series of medicinal plants that would potentially be beneficial in treating SARS-CoV-2 infection according to TPM textbooks. Then, we review medicinal plants based on the pharmacological studies obtained from electronic databases and discuss their mechanism of action in SARS-CoV-2 infection. There are several medicinal plants in TPM with cardiotonic, kidney tonic, and pulmonary tonic activities, protecting the lung, heart, and kidney, the three main vulnerable organs in SARS-CoV-2 infection. Some medicinal plants can prevent “humor infection”, a situation described in TPM which has similar features to SARS-CoV-2 infection. Pharmacological evaluations are in line with the therapeutic activities of several plants mentioned in TPM, mostly through antiviral, cytoprotective, anti-inflammatory, antioxidant, and anti-apoptotic mechanisms. Amongst the primarily-introduced medicinal plants from TPM, rhubarb, licorice, garlic, saffron, galangal, and clove are the most studied plants and represent candidates for clinical studies. The antiviral compounds isolated from these plants provide novel molecular structures to design new semisynthetic antiviral agents. Future clinical studies in healthy volunteers as well as patients suffering from pulmonary infections are necessary to confirm the safety and efficacy of these plants as complementary and integrative interventions in SARS-CoV-2 infection.

scholarly journals An Immune Cell Atlas Reveals Dynamic COVID-19 Specific Neutrophil Programming Amendable to Dexamethasone Therapy

2021 ◽  
Author(s):  
Sarthak Sinha ◽  
Nicole Rosin ◽  
Rohit Arora ◽  
Elodie Labit ◽  
Arzina Jaffer ◽  
...  
Keyword(s):  
Immune Cell ◽  
Therapeutic Interventions ◽  
Cellular Interactions ◽  
Beneficial Effects ◽  
Dexamethasone Therapy ◽  
Life Threatening ◽  
Male Patients ◽  
Novel Coronavirus ◽  
Information Providers

SARS-CoV-2 is a novel coronavirus that causes acute respiratory distress syndrome (ARDS), death and long-term sequelae. Innate immune cells are critical for host defense but are also the primary drivers of ARDS. The relationships between innate cellular responses in ARDS resulting from COVID-19 compared to other causes of ARDS, such as bacterial sepsis is unclear. Moreover, the beneficial effects of dexamethasone therapy during severe COVID-19 remain speculative but understanding the mechanistic effects could improve evidence-based therapeutic interventions. To interrogate these relationships, we developed an scRNAseq atlas that is freely accessible (biernaskielab.ca/COVID_neutrophil). We discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by either interferon (IFN) or prostaglandin (PG) active states. Neutrophils from bacterial ARDS had higher expression of antibacterial molecules such as PLAC8 and CD83. Dexamethasone therapy in COVID patients rapidly altered the IFNactive state, downregulated interferon responsive genes, and activated the IL1R2+ve neutrophils. Dexamethasone also induced the emergence of immature neutrophils expressing immunosuppressive molecules ARG1 and ANXA1, which were not present in healthy controls. Moreover, dexamethasone remodeled global cellular interactions by changing neutrophils from information receivers into information providers. Importantly, male patients had higher proportions of IFN-active neutrophils and a greater degree of steroid-induced immature neutrophil expansion. Indeed, the highest proportion of IFN-active neutrophils was associated with mortality. These results define neutrophil states unique to COVID-19 when contextualized to other life-threatening infections, thereby enhancing the relevance of our findings at the bedside. Furthermore, the molecular benefits of dexamethasone therapy are also defined. The identified molecular pathways can now be targeted to develop improved therapeutics.

Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Vol 27 ◽  
Author(s):  
Sehrish Bano ◽  
Abdul Hameed ◽  
Mariya Al-Rashida ◽  
Shafia Iftikhar ◽  
Jamshed Iqbal
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Structural Features ◽  
Antiviral Drugs ◽  
Rna Dependent Rna Polymerase ◽  
Mortality And Morbidity ◽  
Functional Relationships ◽  
Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

scholarly journals Long-term outcomes after penile prosthesis placement for the Management of Erectile Dysfunction: a single-Centre experience

2021 ◽  
Vol 31 (1) ◽  
Author(s):  
Valentine Frydman ◽  
Ugo Pinar ◽  
Maher Abdessater ◽  
William Akakpo ◽  
Pietro Grande ◽  
...  
Keyword(s):  
Patient Satisfaction ◽  
Erectile Dysfunction ◽  
Penile Prosthesis ◽  
Perioperative Outcomes ◽  
Single Centre ◽  
Satisfactory Outcome ◽  
Single Centre Experience ◽  
Life Threatening ◽  
Few Data

Abstract Background Penile prothesis (PP) is the gold-standard treatment of drug-refractory erectile dysfunction (ED). While postoperative outcomes have been widely described in the literature, there are few data about patient satisfaction and intraoperative events. We aimed to assess long-term patient satisfaction and perioperative outcomes after PP implantation in a single-centre cohort of unselected patients using validated scales. Results A total of 130 patients received a PP (median age: 62.5 years [IQR: 58–69]; median International Index of Erectile Function (IEEF-5) score: 6 [IQR: 5–7]). Median follow-up was 6.3 years [IQR: 4–9.4]. Thirty-two (24.6%) patients underwent surgical revision, of which 20 were PP removals (15.4%). Global PP survival rate was 84.6% and previous PP placement was a risk factor for PP removal (p = 0.02). There were six (4.6%) non-life-threatening intraoperative events including two which resulted in non-placement of a PP (1.5%). EAUiaic grade was 0 for 124 procedures (95.4%), 1 for four procedures (3.1%) and 2 for two procedures (1.5%). Of patients who still had their PP at the end of the study, 91 (80.5%) expressed satisfaction. Conclusions PP implantation is a last-resort treatment for ED with a satisfactory outcome. PPs are well accepted by patients.

scholarly journals Mesenchymal Stem Cells: The Secret Children’s Weapons against the SARS-CoV-2 Lethal Infection

2021 ◽  
Vol 11 (4) ◽  
pp. 1696
Author(s):  
Mario Giosuè Balzanelli ◽  
Pietro Distratis ◽  
Orazio Catucci ◽  
Angelo Cefalo ◽  
Rita Lazzaro ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Respiratory Infections ◽  
Acute Respiratory Infections ◽  
Unusual Event ◽  
Inflammatory Processes ◽  
Life Threatening ◽  
Severe Acute Respiratory Infections ◽  
Novel Coronavirus

Due to the promising effects of mesenchymal stem cells (MSCs) in the treatment of various diseases, this commentary aimed to focus on the auxiliary role of MSCs to reduce inflammatory processes of acute respiratory infections caused by the 2019 novel coronavirus (COVID-19). Since early in 2020, COVID-19, a consequence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly affected millions of people world-wide. The SARS-CoV-2 infection in children appears to be an unusual event. Despite the high number of affected adult and elderly, children and adolescents remained low in amounts, and marginally touched. Based on the promising role of cell therapy and regenerative medicine approaches in the treatment of several life-threatening diseases, it seems that applying MSCs cell-based approaches can also be a hopeful strategy for improving subjects with severe acute respiratory infections caused by COVID-19.

scholarly journals Nanobiocide Based-Silver Nanomaterials Upon Coronaviruses: Approaches for Preventing Viral Infections

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kamyar Khoshnevisan ◽  
Hassan Maleki ◽  
Hadi Baharifar
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Agents ◽  
Long Term Stability ◽  
Silver Nanomaterials ◽  
Inhibitory Mechanisms ◽  
Low Toxicity ◽  
Nano Graphene

Abstract The effectiveness of silver nanomaterials (AgNMs), as antiviral agents, has been confirmed in humans against many different types of viruses. Nanobiocides-based AgNMs can be effectively applied to eliminate coronaviruses (CoVs), as the cause of various diseases in animals and humans, particularly the fatal human respiratory infections. Mostly, these NMs act effectively against CoVs, thanks to the NMs’ fundamental anti-viral structures like reactive oxygen species (ROS), and photo-dynamic and photo-thermal abilities. Particularly, the antiviral activity of AgNMs is clarified under three inhibitory mechanisms including viral entry limitation, attachment inhibition, and viral replication limitation. It is believed that nanobiocide with other possible materials such as TiO2, silica and, carbon NMs exclusively nano-graphene materials can emerge as a more effective disinfectant for long-term stability with low toxicity than common disinfectants. Nanobiocides also can be applied for the prevention and treatment of viral infections specifically against COVID-19. Graphic Abstract

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