scholarly journals Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2306
Author(s):  
Shiu-Wan Chan ◽  
Talha Shafi ◽  
Robert C. Ford
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Cell Entry ◽  
Human Cell Lines ◽  
Structural Homology ◽  
Virus Attachment ◽  
Ic50 Values ◽  
Coronavirus Infection ◽  
Related Compounds ◽  
Infectious Cycle

Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC50 values in the 2–5 μM range, were identified. Further studies demonstrated that these “kite-shaped” molecules were surprisingly specific for SARS-CoV-1 and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover, the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.

scholarly journals Kite-shaped molecules block SARS-CoV-2 cell entry at a post-attachment step

2021 ◽  
Author(s):  
Shiu-Wan Chan ◽  
Talha Shafi ◽  
Robert Ford
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Cell Entry ◽  
Human Cell Lines ◽  
Structural Homology ◽  
Virus Attachment ◽  
Ic50 Values ◽  
Coronavirus Infection ◽  
Related Compounds ◽  
Infectious Cycle

Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC50 values in the 1-5μM range, were identified. Further studies demonstrated that these kite-shaped molecules were surprisingly specific for SARS-CoV and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.

scholarly journals Isolation and Characterization of a Novel Bat Coronavirus Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus

2015 ◽  
Vol 90 (6) ◽  
pp. 3253-3256 ◽  
Author(s):  
Xing-Lou Yang ◽  
Ben Hu ◽  
Bo Wang ◽  
Mei-Niang Wang ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Cell Lines ◽  
Human Cell ◽  
Genomic Sequence ◽  
Cell Entry ◽  
Human Cell Lines ◽  
S Gene ◽  
Isolation And Characterization ◽  
Bat Coronavirus

We report the isolation and characterization of a novel bat coronavirus which is much closer to the severe acute respiratory syndrome coronavirus (SARS-CoV) in genomic sequence than others previously reported, particularly in its S gene. Cell entry and susceptibility studies indicated that this virus can use ACE2 as a receptor and infect animal and human cell lines. Our results provide further evidence of the bat origin of the SARS-CoV and highlight the likelihood of future bat coronavirus emergence in humans.

scholarly journals COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 993
Author(s):  
Renuka Raman ◽  
Krishna J. Patel ◽  
Kishu Ranjan
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Viral Vector ◽  
Therapeutic Strategies ◽  
Convincing Evidence ◽  
Plasma Therapy ◽  
Therapeutic Monoclonal Antibodies ◽  
Increased Susceptibility

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

scholarly journals Asymptomatic Severe Acute Respiratory Syndrome–associated Coronavirus Infection

2003 ◽  
Vol 9 (11) ◽  
pp. 1491-1492 ◽  
Author(s):  
Harold K.K. Lee ◽  
Eugene Y.K. Tso ◽  
T. N. Chau ◽  
Owen T.Y. Tsang ◽  
W. Choi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Coronavirus Infection

scholarly journals Anti-COVID drugs: repurposing existing drugs or search for new complex entities, strategies and perspectives

2020 ◽  
Vol 12 (19) ◽  
pp. 1743-1757
Author(s):  
Anna Pawełczyk ◽  
Lucjusz Zaprutko
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antiviral Activity ◽  
Small Molecules ◽  
Computational Chemistry ◽  
Structural Modification ◽  
Antiviral Agents ◽  
Complex Molecules ◽  
Active Complex ◽  
Novel Virus ◽  
Effective Drugs

At the end of 2019, a novel virus causing severe acute respiratory syndrome to spread globally. There are currently no effective drugs targeting SARS-CoV-2. In this study, based on the analysis of numerous references and selected methods of computational chemistry, the strategy of integrative structural modification of small molecules with antiviral activity into potential active complex molecules has been presented. Proposed molecules have been designed based on the structure of triterpene oleanolic acid and complemented by structures characteristic of selected anti-COVID therapy assisted drugs. Their pharmaceutical molecular parameters and the preliminary bioactivity were calculated and predicted. The results of the above analyses show that among the designed complex substances there are potential antiviral agents directed mainly on SARS-CoV-2.

scholarly journals Seneca Valley virus attachment and uncoating mediated by its receptor anthrax toxin receptor 1

2018 ◽  
Vol 115 (51) ◽  
pp. 13087-13092 ◽  
Author(s):  
Lin Cao ◽  
Ran Zhang ◽  
Tingting Liu ◽  
Zixian Sun ◽  
Mingxu Hu ◽  
...  
Keyword(s):  
Metal Ion ◽  
Structural Changes ◽  
Attachment Site ◽  
Cell Entry ◽  
Anthrax Toxin ◽  
Virus Propagation ◽  
Virus Attachment ◽  
Toxin Receptor ◽  
Seneca Valley Virus ◽  
Acidic Conditions

Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. SVV mediates cell entry by attachment to the receptor anthrax toxin receptor 1 (ANTXR1). Here we determine atomic structures of mature SVV particles alone and in complex with ANTXR1 in both neutral and acidic conditions, as well as empty “spent” particles in complex with ANTXR1 in acidic conditions by cryoelectron microscopy. SVV engages ANTXR1 mainly by the VP2 DF and VP1 CD loops, leading to structural changes in the VP1 GH loop and VP3 GH loop, which attenuate interprotomer interactions and destabilize the capsid assembly. Despite lying on the edge of the attachment site, VP2 D146 interacts with the metal ion in ANTXR1 and is required for cell entry. Though the individual substitution of most interacting residues abolishes receptor binding and virus propagation, a serine-to-alanine mutation at VP2 S177 significantly increases SVV proliferation. Acidification of the SVV–ANTXR1 complex results in a major reconfiguration of the pentameric capsid assemblies, which rotate ∼20° around the icosahedral fivefold axes to form a previously uncharacterized spent particle resembling a potential uncoating intermediate with remarkable perforations at both two- and threefold axes. These structures provide high-resolution snapshots of SVV entry, highlighting opportunities for anticancer therapeutic optimization.

scholarly journals An Update on Animal Models for Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Countermeasure Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Liang Zhang ◽  
Shuaiyin Chen ◽  
Weiguo Zhang ◽  
Haiyan Yang ◽  
Yuefei Jin ◽  
...  
Keyword(s):  
Animal Models ◽  
Severe Acute Respiratory Syndrome ◽  
Research Progress ◽  
Laboratory Mice ◽  
Disease Manifestation ◽  
Highly Pathogenic ◽  
The World ◽  
Coronavirus Infection ◽  
Different Levels ◽  
Critical Aspects

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic since March 2020 and led to significant challenges to over 200 countries and regions all over the world. The establishment of highly pathogenic coronavirus animal model is beneficial for the study of vaccines and pathogenic mechanism of the virus. Laboratory mice, Syrian hamsters, Non-human primates and Ferrets have been used to establish animal models of emerging coronavirus infection. Different animal models can reproduce clinical infection symptoms at different levels. Appropriate animal models are of great significance for the pathogenesis of COVID-19 and the research progress related to vaccines. This review aims to introduce the current progress about experimental animal models for SARS-CoV-2, and collectively generalize critical aspects of disease manifestation in humans and increase their usefulness in research into COVID-19 pathogenesis and developing new preventions and treatments.

scholarly journals A case of severe acute respiratory syndrome coronavirus 2 with acute thrombotic cerebral infarction and generalized thrombosis

2021 ◽  
pp. 405-408
Author(s):  
Sylvia Nikolaeva Genova ◽  
Nikolaeva Genova ◽  
Mina Miroslavova Pencheva ◽  
Alexander Georgiev Ivanov
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Cerebral Infarction ◽  
Viral Pneumonia ◽  
Autopsy Case ◽  
Full Spectrum ◽  
Histological Changes ◽  
Large Size ◽  
Thrombotic Complications ◽  
Coronavirus Infection ◽  
The Brain

The full spectrum of coronavirus disease 2019 (COVID-19) has not been fully described yet. COVID-19 is associated with a high risk of thrombotic complications such as venous thromboembolism and cerebrovascular disease. Here, we report an autopsy case of a 55-year-old woman diagnosed with severe viral pneumonia complicated by acute cerebral infarction and venous and arterial thrombosis in different organs. The patient died due to severe acute respiratory syndrome coronavirus 2. Macroscopically and histologically, in addition to viral pneumonia and diffuse hemorrhages, fibrin clots were found in arteries and venous vessels of medium and large size in the brain, lungs, and pancreas. Propagation of cerebrovascular thrombosis has led to extensive cerebral infarction. The dating of this infarction, according to the macroscopical findings and the histological changes, was between 24 and 48 h before death. This case confirms the hypothesis on the risk of generalized arterial and venous thromboses in coronavirus infection.

scholarly journals SPIKE PROTEIN AND ITS PROTEASES ROLE IN SARS-COV-2 PATHOGENICITY AND TREATMENT; A REVIEW

2021 ◽  
Vol 64 (1) ◽  
Author(s):  
Fateme Tavakoli Far ◽  
◽  
Ehsan Amiri-Ardekani ◽  
Keyword(s):  
Blood Pressure ◽  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Cathepsin B ◽  
Host Cells ◽  
Spike Protein ◽  
Pressure Regulation ◽  
Common Receptor ◽  
The World

Since December 2019, a novel beta coronavirus has spread around the world. This virus can cause severe acute respiratory syndrome (SARS). In this study, we reviewed proteases of SARS-CoV-2 based on related articles published in journals indexed by Scopus, PubMed, and Google Scholar from December 2019 to April 2020. Based on this study, we can claim that this coronavirus has about 76% genotype similarity to SARS coronavirus (SARS-CoV). Also, similarities between these two viruses have been found in the mechanism of entry into host cells and pathogenicity. ACE 2, the angiotensin convertase enzyme 2, plays a role in the Renin-Angiotensin-Aldosterone system (RAAS) and blood pressure regulation. Some mechanisms have been reported for the role of ACE 2 in the pathogenicity of SARS-CoV-2. For example, the interaction between the ACE 2 receptor and spike protein mediated by TMPRSS2, Cathepsin B/L, and other enzymes is responsible for the entry of the virus into human cells and pathogenicity. Some host cell endosomal enzymes are necessary to cleavage coronavirus spike protein and cause binding to their common receptor. So, we conclude that molecules like antibodies or small molecules like ACE 2 antagonists and soluble ACE 2 can be used as a good therapeutic candidate to prevent SARS-CoV-2.

scholarly journals Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen

2020 ◽  
Author(s):  
Maria Kuzikov ◽  
Elisa Costanzi ◽  
Jeanette Reinshagen ◽  
Francesca Esposito ◽  
Laura Vangeel ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Small Molecules ◽  
Drug Target ◽  
Treatment Options ◽  
Cleavage Sites ◽  
X Ray ◽  
Binding Characteristics ◽  
Main Protease ◽  
Ic50 Values

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, and have identified 62 additional compounds with IC50 values below 1 uM and profiled their selectivity towards Chymotrypsin and 3CL-Pro from the MERS virus. A subset of 8 inhibitors showed anti-cytopathic effect in a Vero-E6 cell line and the compounds thioguanosine and MG-132 were analysed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Angs., showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

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