scholarly journals Inhibition of SARS-CoV-2 Entry into Host Cells Using Small Molecules

2020 ◽  
Vol 13 (12) ◽  
pp. 447
Author(s):  
Kenana Al Adem ◽  
Aya Shanti ◽  
Cesare Stefanini ◽  
Sungmun Lee
Keyword(s):  
Small Molecules ◽  
Viral Entry ◽  
High Speed ◽  
Early Stage ◽  
Specific Treatment ◽  
Computational Prediction ◽  
Host Cells ◽  
Viral Fusion ◽  
Respiratory Illnesses ◽  
Lung Failure

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a virus belonging to the Coronavirus family, is now known to cause Coronavirus Disease (Covid-19) which was first recognized in December 2019. Covid-19 leads to respiratory illnesses ranging from mild infections to pneumonia and lung failure. Strikingly, within a few months of its first report, Covid-19 has spread worldwide at an exceptionally high speed and it has caused enormous human casualties. As yet, there is no specific treatment for Covid-19. Designing inhibitory drugs that can interfere with the viral entry process constitutes one of the main preventative therapies that could combat SARS-CoV-2 infection at an early stage. In this review, we provide a brief introduction of the main features of coronaviruses, discuss the entering mechanism of SARS-CoV-2 into human host cells and review small molecules that inhibit SARS-CoV-2 entry into host cells. Specifically, we focus on small molecules, identified by experimental validation and/or computational prediction, that target the SARS-CoV-2 spike protein, human angiotensin converting enzyme 2 (ACE2) receptor and the different host cell proteases that activate viral fusion. Given the persistent rise in Covid-19 cases to date, efforts should be directed towards validating the therapeutic effectiveness of these identified small molecule inhibitors.

Structural Basis for the Understanding of Entry Inhibitors Against SARS Viruses

2021 ◽  
Vol 28 ◽  
Author(s):  
Prem Kumar Kushwaha ◽  
Neha Kumari ◽  
Sneha Nayak ◽  
Keshav Kishor ◽  
Ashoke Sharon
Keyword(s):  
Viral Entry ◽  
Molecular Level ◽  
Virus Entry ◽  
Holistic Approach ◽  
Symptomatic Treatment ◽  
Host Cells ◽  
Structural Basis ◽  
Viral Fusion ◽  
Structural Studies ◽  
Entry Inhibitors

: Outbreaks due to Severe Acute Respiratory Syndrome-Corona virus 2 (SARS-CoV-2) initiated in Wuhan city, China, in December 2019 which continued to spread internationally, posing a pandemic threat as declared by WHO and as of March 10, 2021, confirmed cases reached 118 million along with 2.6 million deaths worldwide. In the absence of specific antiviral medication, symptomatic treatment and physical isolation remain the options to control the contagion. The recent clinical trials on antiviral drugs highlighted some promising compounds such as umifenovir (haemagglutinin-mediated fusion inhibitor), remdesivir (RdRp nucleoside inhibitor), and favipiravir (RdRp Inhibitor). WHO launched a multinational clinical trial on several promising analogs as a potential treatment to combat SARS infection. This situation urges a holistic approach to invent safe and specific drugs as a prophylactic and therapeutic cure for SARS-related-viral diseases, including COVID-19. : It is significant to note that researchers worldwide have been doing their best to handle the crisis and have produced an extensive and promising literature body. It opens a scope and allows understanding the viral entry at the molecular level. A structure-based approach can reveal the molecular-level understanding of viral entry interaction. The ligand profiling and non-covalent interactions among participating amino-acid residues are critical information to delineate a structural interpretation. The structural investigation of SARS virus entry into host cells will reveal the possible strategy for designing drugs like entry inhibitors. : The structure-based approach demonstrates details at the 3D molecular level. It shows specificity about SARS-CoV-2 spike interaction, which uses human angiotensin-converting enzyme 2 (ACE2) as a receptor for entry, and the human protease completes the process of viral fusion and infection. : The 3D structural studies reveal the existence of two units, namely S1 and S2. S1 is called a receptor-binding domain (RBD) and responsible for interacting with the host (ACE2), and the S2 unit participates in the fusion of viral and cellular membranes. TMPRSS2 mediates the cleavage at S1/S2 subunit interface in S-protein of SARS CoV-2, leading to viral fusion. Conformational difference associated with S1 binding alters ACE2 interaction and inhibits viral fusion. Overall, the detailed 3D structural studies help understand the 3D structural basis of interaction between viruses with host factors and available scope for the new drug discovery process targeting SARS-related virus entry into the host cell.

scholarly journals Conserved Oligomeric Golgi (COG) Complex Proteins Facilitate Orthopoxvirus Entry, Fusion and Spread

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 707 ◽  
Author(s):  
Susan Realegeno ◽  
Lalita Priyamvada ◽  
Amrita Kumar ◽  
Jessica B. Blackburn ◽  
Claire Hartloge ◽  
...  
Keyword(s):  
Viral Entry ◽  
Membrane Trafficking ◽  
Gene Knockout ◽  
Host Cells ◽  
Viral Fusion ◽  
Genetic Screens ◽  
Viral Spread ◽  
Cog Complex ◽  
Conserved Oligomeric Golgi ◽  
The Individual

Although orthopoxviruses (OPXV) are known to encode a majority of the genes required for replication in host cells, genome-wide genetic screens have revealed that several host pathways are indispensable for OPXV infection. Through a haploid genetic screen, we previously identified several host genes required for monkeypox virus (MPXV) infection, including the individual genes that form the conserved oligomeric Golgi (COG) complex. The COG complex is an eight-protein (COG1–COG8) vesicle tethering complex important for regulating membrane trafficking, glycosylation enzymes, and maintaining Golgi structure. In this study, we investigated the role of the COG complex in OPXV infection using cell lines with individual COG gene knockout (KO) mutations. COG KO cells infected with MPXV and vaccinia virus (VACV) produced small plaques and a lower virus yield compared to wild type (WT) cells. In cells where the KO phenotype was reversed using a rescue plasmid, the size of virus plaques increased demonstrating a direct link between the decrease in viral spread and the KO of COG genes. KO cells infected with VACV displayed lower levels of viral fusion and entry compared to WT suggesting that the COG complex is important for early events in OPXV infection. Additionally, fewer actin tails were observed in VACV-infected KO cells compared to WT. Since COG complex proteins are required for cellular trafficking of glycosylated membrane proteins, the disruption of this process due to lack of individual COG complex proteins may potentially impair the virus-cell interactions required for viral entry and egress. These data validate that the COG complex previously identified in our genetic screens plays a role in OPXV infection.

scholarly journals Ultrastructural insight into SARS-CoV-2 attachment, entry and budding in human airway epithelium

2021 ◽  
Author(s):  
Andreia L Pinto ◽  
Ranjit K Rai ◽  
Jonathan C Brown ◽  
Paul Griffin ◽  
James R Edgar ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Viral Entry ◽  
Airway Epithelium ◽  
Host Cells ◽  
Apical Plasma Membrane ◽  
Viral Fusion ◽  
Cellular Models ◽  
Ultrastructural Studies ◽  
Human Airway ◽  
Human Airway Epithelium

AbstractUltrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Many studies are limited by the lack of access to appropriate cellular models. As the airway epithelium is the primary site of infection it is essential to study SARS-CoV-2 infection of these cells. Here, we examined human airway epithelium, grown as highly differentiated air-liquid interface cultures and infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant (Variant of Concern 202012/01) by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Two key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistent with these observations, extracellular virions were frequently seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion at the apical plasma membrane demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Profiles strongly suggesting viral budding from the membrane was observed in these compartments and this may explain how virions gain their S glycoprotein containing envelope.

scholarly journals SARS-CoV-2 Entry Inhibitors: Small Molecules and Peptides Targeting Virus or Host Cells

2020 ◽  
Vol 21 (16) ◽  
pp. 5707 ◽  
Author(s):  
Rolando Cannalire ◽  
Irina Stefanelli ◽  
Carmen Cerchia ◽  
Andrea R. Beccari ◽  
Sveva Pelliccia ◽  
...  
Keyword(s):  
Small Molecules ◽  
Viral Entry ◽  
Viral Infections ◽  
Host Factors ◽  
Host Cells ◽  
S Protein ◽  
Entry Inhibitors ◽  
Heptad Repeats ◽  
Direct Acting ◽  
Complementary Strategy

The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.

scholarly journals Lysosomotropic Active Compounds—Hidden Protection against COVID-19 / SARS-CoV-2 Infection?

2020 ◽  
Author(s):  
Markus Blaess ◽  
Lars Kaiser ◽  
Martin Sauer ◽  
Hans-Peter Deigner
Keyword(s):  
Small Molecules ◽  
Viral Entry ◽  
Influenza A ◽  
Viral Infections ◽  
Cathepsin L ◽  
Disease Process ◽  
Host Cells ◽  
Promising Candidate ◽  
Lysosomal Ph ◽  
Common Skin

The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in recent decades, and it is infecting and killing increasing numbers of people every day. In this paper, we discuss the possible relationships among lysosomotropism, increasing lysosomal pH, and the SARS-CoV-2 infection and disease process, and we deduce a possible approach for treatment and prophylaxis. Lysosomotropism is a biological characteristic of small molecules, such as (hydroxyl)chloroquine, amitriptyline, NB 06, or sertraline, which is present in addition to intrinsic receptor-mediated or enzymatic pharmacological effects. Lysosomotropic compounds affect prominent inflammatory messengers, such as IL1B, CCL4, CCL20, and IL6, as well as cathepsin L dependent viral entry (fusion) into host cells. Therefore, this heterogeneous group of compounds is a promising candidate for the prevention and treatment of SARS-CoV-2 infections, as well as influenza A infections and cytokine release syndrome (CRS) triggered by bacterial or viral infections. Patients who have already taken medications with lysosomotropic compounds for other pre-existing conditions may benefit from this treatment in the COVID-19 pandemic. Increased lysosomal pH levels play an important role in the disease process in common skin disorders, such as psoriasis and atopic dermatitis, thus suggesting that affected individuals might benefit from their particular conditions in the COVID-19 pandemic. We suggest data analysis of patients with these diseases, and who are treated with lysosomotropic compounds, and, if the results are promising, subsequent clinical testing of off-label therapy with clinically approved lysosomotropic compounds in the current COVID-19 pandemic and future influenza A pandemics.

scholarly journals FUNCTION AND MECHANISM OF ANGIOTENSIN-CONVERTING ENZYME-2 RECEPTOR TO TRANSPORT SARS-COV-2 INTO THE HOST CELLS―A REVIEW

2020 ◽  
Vol 8 (Spl-1-SARS-CoV-2) ◽  
pp. S190-S201
Author(s):  
Muhammad Bilal ◽  
◽  
Muhammad Iqbal Sarfaraz ◽  
Muhammad Iqbal Husnain ◽  
Nimra Sardar ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Viral Entry ◽  
Host Cells ◽  
Lung Cells ◽  
The Novel ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Lung Failure ◽  
Novel Coronavirus ◽  
Severe Lung

Novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly spread across the world. SARS-CoV-2 is viewed as a continuous global health threat resulting in an alarming number of fatalities worldwide. Angiotensin-converting enzyme-2 (ACE2) has been recognized as one of the vital receptors for the SARS-CoV-2, leading to viral entry into the host cells. It also helps many other receptors, which initiate the entry of SARS-CoV-2 in the host body. A variety of proteins and enzymes are involved in triggering the transport mechanism. The route of viral infection depends on the distribution and expression of receptors, as the virus reaches the cell by binding to cell receptors to complete intracellular replication, virus release, and cause cytotoxicity. In addition to alveolar lung tissues, ACE2 also plays a pivotal role in other organs. Due to the abundant presence in lung cells, SARS-CoV-2 mostly affects the lungs and causes their destruction. The spike protein utilizes the digestion of ACE2, which strongly contributes to the pathogenesis of severe lung failure. Different experiments show that ACE2 not only helps the virus to migrate in the host cell but also allow us to fight against this pandemic disease. This review article summarizes the current progress that highlights the critical biological functionalities and mechanisms of ACE2 as the novel receptor to transport SARS-CoV-2 into host cells matrix.

scholarly journals An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen

2020 ◽  
Author(s):  
Yao Yao ◽  
Rameshwar U. Kadam ◽  
Chang-Chun David Lee ◽  
Jordan L. Woehl ◽  
Nicholas C. Wu ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Viral Entry ◽  
Fluorescence Polarization ◽  
Influenza A ◽  
Cyclic Peptide ◽  
Host Cells ◽  
Influenza Hemagglutinin ◽  
Group 1

AbstractInfluenza hemagglutinin (HA) glycoprotein is the primary surface antigen targeted by the host immune response and a focus for development of novel vaccines, broadly neutralizing antibodies (bnAbs) and therapeutics. HA enables viral entry into host cells via receptor binding and membrane fusion and is a validated target for drug discovery. However, to date, only a very few bona fide small molecules have been reported against the HA. To identity new antiviral lead candidates against the highly conserved fusion machinery in the HA stem, we synthesized a fluorescence-polarization probe based on a recently described neutralizing cyclic peptide P7 derived from the complementarity-determining region loops of human bnAbs FI6v3 and CR9114 against the HA stem. We then designed a robust binding assay compatible with high-throughput screening to identify molecules with low μM to nM affinity to influenza A group 1 HAs. Our simple, low-cost, and efficient in vitro assay was used to screen H1/Puerto Rico/8/1934 HA trimer against approximately 72,000 compounds. The crystal structure of H1/Puerto Rico/8/1934 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets in the HA stem similar to bnAbs FI6v3 and CR9114, cyclic peptide P7, and small molecule inhibitor JNJ4796. F0045 is enantioselective against a panel of group 1 HAs and F0045(S) exhibits in vitro neutralization activity against multiple H1N1 and H5N1 strains. Our assay, compound characterization, and small-molecule candidate should further stimulate the discovery and development of new compounds with unique chemical scaffolds and enhanced influenza antiviral capabilities.SummaryInfluenza hemagglutinin (HA) glycoprotein enables viral entry into host cells and is the main target for antibodies in our immune system. While HA has now been established as a validated target for drug discovery, no FDA-approved small molecules are available that specifically prevent HA from binding host receptors or inhibit its membrane fusion activity and thus prevent infection. We therefore designed a fluorescence polarization probe to enable rapid identification of small molecules that bind to the stem fusion machinery of group 1 HAs. Application of our assay yielded a small molecule to the influenza A group 1 HA stem with antiviral efficacy.

APPLICATION OF THE EARLY DAMAGE DIAGNOSTICS TECHNIQUE TO EXAMINATION OF THE AVIATION PANEL

2019 ◽  
Vol 85 (6) ◽  
pp. 53-63 ◽  
Author(s):  
I. E. Vasil’ev ◽  
Yu. G. Matvienko ◽  
A. V. Pankov ◽  
A. G. Kalinin
Keyword(s):  
Acoustic Emission ◽  
Damage Detection ◽  
High Speed ◽  
Early Stage ◽  
Video Data ◽  
High Speed Video ◽  
Damage Diagnostics ◽  
Subsurface Defect ◽  
Sensitive Coating ◽  
Early Damage

The results of using early damage diagnostics technique (developed in the Mechanical Engineering Research Institute of the Russian Academy of Sciences (IMASH RAN) for detecting the latent damage of an aviation panel made of composite material upon bench tensile tests are presented. We have assessed the capabilities of the developed technique and software regarding damage detection at the early stage of panel loading in conditions of elastic strain of the material using brittle strain-sensitive coating and simultaneous crack detection in the coating with a high-speed video camera “Video-print” and acoustic emission system “A-Line 32D.” When revealing a subsurface defect (a notch of the middle stringer) of the aviation panel, the general concept of damage detection at the early stage of loading in conditions of elastic behavior of the material was also tested in the course of the experiment, as well as the software specially developed for cluster analysis and classification of detected location pulses along with the equipment and software for simultaneous recording of video data flows and arrays of acoustic emission (AE) data. Synchronous recording of video images and AE pulses ensured precise control of the cracking process in the brittle strain-sensitive coating (tensocoating)at all stages of the experiment, whereas the use of structural-phenomenological approach kept track of the main trends in damage accumulation at different structural levels and identify the sources of their origin when classifying recorded AE data arrays. The combined use of oxide tensocoatings and high-speed video recording synchronized with the AE control system, provide the possibility of definite determination of the subsurface defect, reveal the maximum principal strains in the area of crack formation, quantify them and identify the main sources of AE signals upon monitoring the state of the aviation panel under loading P = 90 kN, which is about 12% of the critical load.

SARS-CoV-2 Biology Insights, Part IV.Antibody-Dependent Enhancement (ADE) and the tricky “Herd Immunity”: narrative review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Whooping Cough ◽  
Common Knowledge ◽  
Herd Immunity ◽  
Life Quality ◽  
Host Cells ◽  
System P

BACKGROUND It is common knowledge that vaccination has improved our life quality and expectancy since it succeeded in achieving almost eradication of several diseases including chickenpox (varicella), diphtheria, hepatitis A and B, measles, meningococcal, mumps, pneumococcal, polio, rotavirus, rubella, tetanus and whooping cough (pertussis) Vaccination success is based on vaccine induction of neutralizing antibodies that help fight the infection (e.g. by a virus), preventing the disease. Conversely, Antibody-dependent enhancement (ADE) of a viral infection occurs when anti-viral antibodies facilitate viral entry into host cells and enhance viral infection in these cells. ADE has been previously studied in Dengue and HIV viruses and explains why a second infection with Dengue can be lethal. As already reviewed in Part I and Part II, SARS-Cov-2 shares with HIV not only 4 sequences in the Spike protein but also the capacity to attack the immune system. OBJECTIVE As HIV presents ADE, we wondered whether this was also the case regarding SARS-CoV-2. METHODS A literature review was done through Google. RESULTS SARS-CoV-2 presents ADE. As SARS, which does not have the 4 HIV-like inserts, has the same property, ADE would not be driven by the HIV-like spike sequences. CONCLUSIONS ADE can explain the failure of herd immunity-based strategies and will also probably hamper anti-SARS-CoV-2 vaccine development. As reviewed in Part I, there fortunately are promising therapeutic strategies for COVID-19, which should be further developed. In the meantime, complementary countermeasures to protect mainly the youth from this infection are presented to be discussed in Part V Viewpoint.

scholarly journals SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Dimitris G. Placantonakis ◽  
Maria Aguero-Rosenfeld ◽  
Abdallah Flaifel ◽  
John Colavito ◽  
Kenneth Inglima ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Viral Entry ◽  
Cell Types ◽  
Host Cells ◽  
Nasopharyngeal Swab ◽  
Rt Pcr ◽  
Neurologic Sequelae ◽  
Show Evidence ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.

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