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.

An Updated Review on Betacoronavirus Viral Entry Inhibitors: Learning from Past Discoveries to Advance COVID-19 Drug Discovery

2021 ◽  
Vol 21 ◽  
Author(s):  
Dima A. Sabbah ◽  
Rima Hajjo ◽  
Sanaa K. Bardaweel ◽  
Haizhen A. Zhong
Keyword(s):  
Viral Entry ◽  
Clinical Importance ◽  
Structural Features ◽  
Biomedical Literature ◽  
Host Cells ◽  
Virus Binding ◽  
Structural Determinants ◽  
S Protein ◽  
Host Tropism ◽  
Entry Inhibitors

: One year after its first outbreak reported in China, coronavirus disease 2019 (COVID-19) pandemic is still sweeping the World causing serious infections and claiming more fatalities. COVID-19 is caused by the novel corona virus SARS-CoV-2, which belongs to the genus Betacoronavirus (β-CoVs) which is of greatest clinical importance since it contains many other viruses that cause respiratory disease in humans including OC43, HKU1, SARS-CoV and MERS. The spike (S) glycoprotein of β-CoVs is a key virulence factor determining disease pathogenesis and host tropism, and it also mediates virus binding to host’s receptors to allow viral entry into host cells, i.e., the first step in virus lifecycle. This, viral entry inhibitors are considered promising putative drugs for COVID-19. Herein, we mined the biomedical literature for viral entry inhibitors of other corona viruses, with special emphasis on β-CoVs entry inhibitors. We also outlined the structural features of SARS-CoV-2 S protein and how it differs from other β-CoVs to better understand the structural determinants of S protein binding to its human receptor (ACE2). This review highlighted several promising viral entry inhibitors as potential treatments for COVID-19.

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 Amino Acids 1055 to 1192 in the S2 Region of Severe Acute Respiratory Syndrome Coronavirus S Protein Induce Neutralizing Antibodies: Implications for the Development of Vaccines and Antiviral Agents

2005 ◽  
Vol 79 (6) ◽  
pp. 3289-3296 ◽  
Author(s):  
Choong-Tat Keng ◽  
Aihua Zhang ◽  
Shuo Shen ◽  
Kuo-Ming Lip ◽  
Burtram C. Fielding ◽  
...  
Keyword(s):  
Amino Acids ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Antiviral Agents ◽  
Host Cells ◽  
Heptad Repeat ◽  
Antigenic Determinants ◽  
Amino Acid Residues ◽  
S Protein

ABSTRACT The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) interacts with cellular receptors to mediate membrane fusion, allowing viral entry into host cells; hence it is recognized as the primary target of neutralizing antibodies, and therefore knowledge of antigenic determinants that can elicit neutralizing antibodies could be beneficial for the development of a protective vaccine. Here, we expressed five different fragments of S, covering the entire ectodomain (amino acids 48 to 1192), as glutathione S-transferase fusion proteins in Escherichia coli and used the purified proteins to raise antibodies in rabbits. By Western blot analysis and immunoprecipitation experiments, we showed that all the antibodies are specific and highly sensitive to both the native and denatured forms of the full-length S protein expressed in virus-infected cells and transfected cells, respectively. Indirect immunofluorescence performed on fixed but unpermeabilized cells showed that these antibodies can recognize the mature form of S on the cell surface. All the antibodies were also able to detect the maturation of the 200-kDa form of S to the 210-kDa form by pulse-chase experiments. When the antibodies were tested for their ability to inhibit SARS-CoV propagation in Vero E6 culture, it was found that the anti-SΔ10 antibody, which was targeted to amino acid residues 1029 to 1192 of S, which include heptad repeat 2, has strong neutralizing activities, suggesting that this region of S carries neutralizing epitopes and is very important for virus entry into cells.

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 Aptamers in Virology—A Consolidated Review of the Most Recent Advancements in Diagnosis and Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1646
Author(s):  
Tejabhiram Yadavalli ◽  
Ipsita Volety ◽  
Deepak Shukla
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
High Specificity ◽  
Host Cells ◽  
Short Oligonucleotide ◽  
The Past ◽  
Viral Antigens ◽  
Diagnosis And Therapy ◽  
Viral Diagnosis ◽  
Made In

The use of short oligonucleotide or peptide molecules as target-specific aptamers has recently garnered substantial attention in the field of the detection and treatment of viral infections. Based on their high affinity and high specificity to desired targets, their use is on the rise to replace antibodies for the detection of viruses and viral antigens. Furthermore, aptamers inhibit intracellular viral transcription and translation, in addition to restricting viral entry into host cells. This has opened up a plethora of new targets for the research and development of novel vaccines against viruses. Here, we discuss the advances made in aptamer technology for viral diagnosis and therapy in the past decade.

scholarly journals Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

2020 ◽  
Author(s):  
Micholas Smith ◽  
Jeremy C. Smith
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Protein S ◽  
Host Cells ◽  
Spike Protein ◽  
The Novel ◽  
S Protein ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

The novel Wuhan coronavirus (SARS-CoV-2) has been sequenced, and the virus shares substantial similarity with SARS-CoV. Here, using a computational model of the spike protein (S-protein) of SARS-CoV-2 interacting with the human ACE2 receptor, we make use of the world's most powerful supercomputer, SUMMIT, to enact an ensemble docking virtual high-throughput screening campaign and identify small-molecules which bind to either the isolated Viral S-protein at its host receptor region or to the S protein-human ACE2 interface. We hypothesize the identified small-molecules may be repurposed to limit viral recognition of host cells and/or disrupt host-virus interactions. A ranked list of compounds is given that can be tested experimentally.<br>

scholarly journals Cathepsins: innate immune proteases that regulate viral entry into host cells

2018 ◽  
Vol 72 ◽  
pp. 253-263 ◽  
Author(s):  
Magdalena Bossowska-Nowicka ◽  
Felix N. Toka ◽  
Matylda Mielcarska ◽  
Lidia Szulc-Dąbrowska
Keyword(s):  
Viral Entry ◽  
Antigen Processing ◽  
Viral Infections ◽  
Innate Immune ◽  
Host Cells ◽  
Human Pathogens ◽  
Cellular Mechanisms ◽  
Cathepsin Proteases ◽  
Cell Adhesion And Migration

Cathepsins are group of endolysosomal proteases that regulate the mechanisms of innate and adaptive immunity, including cell adhesion and migration, antigen processing and presentation and resistance to several viral infections. Some cathepsins are required for Toll-like receptor (TLR)3, TLR7 and TLR9 cleavage and the formation of functional receptors that participate in sensing viral nucleic acids. Moreover, cathepsins directly stimulate or inhibit cytokine secretion involved in the regulation of antiviral innate immune response. Recent findings underline the important role of cathepsins in the entry of filoviruses, reoviruses, retroviruses and other types of viruses into the host cell. Many enveloped viruses require the presence of cathepsins for efficient fusion with membranes of infected cells, and the inhibition of their activity results in a significant reduction of virus replication. In addition, many viruses utilize conserved cellular mechanisms, such as endocytosis or low pH within the endosome, for efficient penetration into the cell interior, disassembly of viral capsid, and other stages of productive viral replication cycle. Therefore, a better understanding of the functional role of cathepsin proteases in the pathogenesis of viral infections should lead to the development of novel therapeutics for a variety of particularly dangerous human pathogens.

scholarly journals Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

2020 ◽  
Author(s):  
Micholas Smith ◽  
Jeremy C. Smith
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Protein S ◽  
Host Cells ◽  
Spike Protein ◽  
The Novel ◽  
S Protein ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

The novel Wuhan coronavirus (SARS-CoV-2) has been sequenced, and the virus shares substantial similarity with SARS-CoV. Here, using a computational model of the spike protein (S-protein) of SARS-CoV-2 interacting with the human ACE2 receptor, we make use of the world's most powerful supercomputer, SUMMIT, to enact an ensemble docking virtual high-throughput screening campaign and identify small-molecules which bind to either the isolated Viral S-protein at its host receptor region or to the S protein-human ACE2 interface. We hypothesize the identified small-molecules may be repurposed to limit viral recognition of host cells and/or disrupt host-virus interactions. A ranked list of compounds is given that can be tested experimentally.<br>

scholarly journals An aptamer/ siRNA Chimera against The SARS-CoV-2: A Dual Therapeutic Strategy for The Virus Neutralizing and RNA Interfering

2020 ◽  
Author(s):  
Javad Khanali ◽  
Mohammadreza Azangou-khyavy ◽  
Yasaman Asaadi ◽  
Monire Jamalkhah ◽  
Jafar Kiani
Keyword(s):  
Viral Entry ◽  
Targeted Delivery ◽  
Therapeutic Strategy ◽  
Therapeutic Targets ◽  
Rna Degradation ◽  
Host Cells ◽  
Gene Knockdown ◽  
Small Interfering Rnas ◽  
S Protein ◽  
Viral Genes

Abstract During the ongoing COVID-19 pandemic, besides the vaccines, there is an urgent need for the development of effective therapeutics. Although significant efforts have been made to develop such therapies, there are currently no approved treatments for COVID-19. One of the potential therapeutic targets is the spike (S) protein of SARS-CoV-2, which mediates viral entry into host cells. It has been shown that targeting S protein could neutralize viruses and hinder their binding to the cells. Among known viral neutralizing agents, aptamers’ potential in neutralizing the SARS-Cov-2 virus has not yet been revealed. In addition, aptamers could also be used for targeted delivery of drugs and other genetic elements, such as siRNAs, to the cells. Small interfering RNAs (siRNAs) are reliable tools for gene knockdown via RNA degradation. siRNAs have been implemented previously against some viruses, including SARS-CoV, to target its genome. Recently, potential siRNA sequences and their targets in the SARS-CoV-2 genome have been reported, and the efficiency of siRNAs in inhibiting SARS-CoV-2 infection is being revealed. An alternative antiviral approach we propose here relies on an aptamer-siRNA-based system for the treatment of COVID-19. These aptamers could neutralize viruses by hindering their receptor-mediated endocytosis, and siRNAs could suppress the expression of viral genes and halt various aspects of its pathogenesis whenever the aptamers fail to neutralize the virus.

SARS-CoV-2 Entry inhibitors targeting virus-ACE2 or virus-TMPRSS2 interactions

2021 ◽  
Vol 28 ◽  
Author(s):  
Hao Lin ◽  
Srinivasulu Cherukupalli ◽  
Da Feng ◽  
Shenghua Gao ◽  
Dongwei Kang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Entry Inhibitors ◽  
Concise Report ◽  
Surface Receptor ◽  
Transmembrane Serine Protease

: COVID-19 is an infectious disease caused by SARS-CoV-2. The life cycle of SARS-CoV-2 includes the entry into the target cells, replicase translation, replicating and transcribing genomes, translating structural proteins, assembling and releasing new virions. Entering host cells is a crucial stage in the early life cycle of the virus, and blocking this stage can effectively prevent virus infection. SARS enters the target cells mediated by the interaction between the viral S protein and the target cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the cleavage effect of type-II transmembrane serine protease (TMPRSS2) on the S protein. Therefore, the ACE2 receptor and TMPRSS2 are important targets for SARS-CoV-2 entry inhibitors. Herein, we provide a concise report/information on drugs with potential therapeutic value targeting virus-ACE2 or virus-TMPRSS2 interactions, to provide a reference for the design and discovery of potential entry inhibitors against SARS-CoV-2.

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