scholarly journals Structural analysis of SARS-CoV-2 genome and predictions of the human interactome

2020 ◽  
Vol 48 (20) ◽  
pp. 11270-11283 ◽  
Author(s):  
Andrea Vandelli ◽  
Michele Monti ◽  
Edoardo Milanetti ◽  
Alexandros Armaos ◽  
Jakob Rupert ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Viral Entry ◽  
Viral Infections ◽  
Host Cells ◽  
Structural Level ◽  
Rna Helicases ◽  
Human Interactome ◽  
Viral Genomes ◽  
Human Proteins ◽  
Genomic Regions

Abstract Specific elements of viral genomes regulate interactions within host cells. Here, we calculated the secondary structure content of >2000 coronaviruses and computed >100 000 human protein interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genomic regions display different degrees of conservation. SARS-CoV-2 domain encompassing nucleotides 22 500–23 000 is conserved both at the sequence and structural level. The regions upstream and downstream, however, vary significantly. This part of the viral sequence codes for the Spike S protein that interacts with the human receptor angiotensin-converting enzyme 2 (ACE2). Thus, variability of Spike S is connected to different levels of viral entry in human cells within the population. Our predictions indicate that the 5′ end of SARS-CoV-2 is highly structured and interacts with several human proteins. The binding proteins are involved in viral RNA processing, include double-stranded RNA specific editases and ATP-dependent RNA-helicases and have strong propensity to form stress granules and phase-separated assemblies. We propose that these proteins, also implicated in viral infections such as HIV, are selectively recruited by SARS-CoV-2 genome to alter transcriptional and post-transcriptional regulation of host cells and to promote viral replication.

scholarly journals Structural analysis of SARS-CoV-2 genome and predictions of the human interactome

2020 ◽  
Author(s):  
Andrea Vandelli ◽  
Michele Monti ◽  
Edoardo Milanetti ◽  
Alexandros Armaos ◽  
Jakob Rupert ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Viral Entry ◽  
Viral Infections ◽  
Host Cells ◽  
Structural Level ◽  
Rna Helicases ◽  
Human Interactome ◽  
Viral Genomes ◽  
Human Proteins ◽  
Genomic Regions

ABSTRACTSpecific elements of viral genomes regulate interactions within host cells. Here, we calculated the secondary structure content of >2000 coronaviruses and computed >100000 human protein interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genomic regions display different degrees of conservation. SARS-CoV-2 domain encompassing nucleotides 22500 – 23000 is conserved both at the sequence and structural level. The regions upstream and downstream, however, vary significantly. This part codes for the Spike S protein that interacts with the human receptor angiotensin-converting enzyme 2 (ACE2). Thus, variability of Spike S may be connected to different levels of viral entry in human cells within the population.Our predictions indicate that the 5’ end of SARS-CoV-2 is highly structured and interacts with several human proteins. The binding proteins are involved in viral RNA processing such as double-stranded RNA specific editases and ATP-dependent RNA-helicases and have strong propensity to form stress granules and phase-separated complexes. We propose that these proteins, also implicated in viral infections such as HIV, are selectively recruited by SARS-CoV-2 genome to alter transcriptional and post-transcriptional regulation of host cells and to promote viral replication.

scholarly journals H2V, a Database for Human Proteins and Genes in Response to SARS-CoV-2, SARS-CoV, and MERS-CoV Infection

2020 ◽  
Author(s):  
Nan Zhou ◽  
Jinku Bao ◽  
Yuping Ning
Keyword(s):  
Differentially Expressed Genes ◽  
Protein Interactions ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Differentially Expressed ◽  
Easy Access ◽  
Differentially Expressed Proteins ◽  
Protein Protein Interactions ◽  
Associated Proteins ◽  
Human Proteins

Abstract The ongoing COVID-19 pandemic in the world is caused by SARS-CoV-2, a new coronavirus firstly discovered in the end of 2019. It has led to more than 10 million confirmed cases and more than 500,000 confirmed deaths across 216 countries by 1 July 2020, according to WHO statistics. SARS-CoV-2, SARS-CoV, and MERS-CoV are alike, killing people, impairing economy, and inflicting long-term impacts on the society. However, no specific drug or vaccine has been approved as a cure for these viruses. The efforts to develop antiviral measures are hampered by insufficient understanding of molecular responses of human to viral infections. In this study, we collected experimentally validated human proteins that interact with SARS-CoV-2 proteins, human proteins whose expression, translation and phosphorylation levels experience significantly changes after SARS-CoV-2 or SARS-CoV infection, human proteins that correlate with COVID-19 severity, and human genes whose expression levels significantly changed upon SARS-CoV-2 or MERS-CoV infection. A database, H2V, was then developed for easy access to these data. Currently H2V includes: 332 human-SARS-CoV-2 protein-protein interactions; 65 differentially expressed proteins, 232 differentially translated proteins, 1298 differentially phosphorylated proteins, 204 severity associated proteins, and 4012 differentially expressed genes responding to SARS-CoV-2 infection; 66 differentially expressed proteins responding to SARS-CoV infection; and 6981 differentially expressed genes responding to MERS-CoV infection. H2V can help to understand the cellular responses associated with SARS-CoV-2, SARS-CoV and MERS-CoV infection. It is expected to speed up the development of antiviral agents and shed light on the preparation for potential coronavirus emergency in the future.Database url: http://www.zhounan.org/h2v

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 Multi-schema computational prediction of the comprehensive SARS-CoV-2 vs. human interactome

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11117
Author(s):  
Kevin Dick ◽  
Anand Chopra ◽  
Kyle K. Biggar ◽  
James R. Green
Keyword(s):  
Protein Interactions ◽  
Scientific Community ◽  
Predictive Performance ◽  
Computational Prediction ◽  
Viral Disease ◽  
High Confidence ◽  
Human Interactome ◽  
Holistic Understanding ◽  
Human Proteins ◽  
Novel Coronavirus

Background Understanding the disease pathogenesis of the novel coronavirus, denoted SARS-CoV-2, is critical to the development of anti-SARS-CoV-2 therapeutics. The global propagation of the viral disease, denoted COVID-19 (“coronavirus disease 2019”), has unified the scientific community in searching for possible inhibitory small molecules or polypeptides. A holistic understanding of the SARS-CoV-2 vs. human inter-species interactome promises to identify putative protein-protein interactions (PPI) that may be considered targets for the development of inhibitory therapeutics. Methods We leverage two state-of-the-art, sequence-based PPI predictors (PIPE4 & SPRINT) capable of generating the comprehensive SARS-CoV-2 vs. human interactome, comprising approximately 285,000 pairwise predictions. Three prediction schemas (all, proximal, RP-PPI) are leveraged to obtain our highest-confidence subset of PPIs and human proteins predicted to interact with each of the 14 SARS-CoV-2 proteins considered in this study. Notably, the use of the Reciprocal Perspective (RP) framework demonstrates improved predictive performance in multiple cross-validation experiments. Results The all schema identified 279 high-confidence putative interactions involving 225 human proteins, the proximal schema identified 129 high-confidence putative interactions involving 126 human proteins, and the RP-PPI schema identified 539 high-confidence putative interactions involving 494 human proteins. The intersection of the three sets of predictions comprise the seven highest-confidence PPIs. Notably, the Spike-ACE2 interaction was the highest ranked for both the PIPE4 and SPRINT predictors with the all and proximal schemas, corroborating existing evidence for this PPI. Several other predicted PPIs are biologically relevant within the context of the original SARS-CoV virus. Furthermore, the PIPE-Sites algorithm was used to identify the putative subsequence that might mediate each interaction and thereby inform the design of inhibitory polypeptides intended to disrupt the corresponding host-pathogen interactions. Conclusion We publicly released the comprehensive sets of PPI predictions and their corresponding PIPE-Sites landscapes in the following DataVerse repository: https://www.doi.org/10.5683/SP2/JZ77XA. The information provided represents theoretical modeling only and caution should be exercised in its use. It is intended as a resource for the scientific community at large in furthering our understanding of SARS-CoV-2.

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 In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

2021 ◽  
Author(s):  
Amruta Narayanappa ◽  
Elizabeth B Engler-Chiurazzi ◽  
Isabel C Murray-Brown ◽  
Timothy E Gressett ◽  
Ifechukwude J Biose ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Viral Entry ◽  
Therapeutic Potential ◽  
Host Cells ◽  
Spike Protein ◽  
Cell Infection ◽  
Integrin Alpha5beta1 ◽  
Chemokine Ligand

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin alpha5beta1 and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

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.

Viral Life History Traits

2016 ◽  
Author(s):  
Joshua S. Weitz
Keyword(s):  
Life History ◽  
Mortality Rate ◽  
Host Cell ◽  
Life History Traits ◽  
Viral Infections ◽  
Burst Size ◽  
Host Cells ◽  
Viral Genomes ◽  
Life History Stages ◽  
Viral Progeny

This chapter discusses a number of key commonalities and differences among viral life history traits. Viruses have two key life history stages: inside and outside a host cell. Viral infections of microbes often lead to the death of host cells and the release of viral progeny. Viral infections can also lead to the integration of viral genomes with those of their hosts; induction of these genomes can result in subsequent lysis and release of viral progeny. Viruses are distinguished not only by the host they infect but also by the quantitative rates and levels at which these interactions take place. Viral life history traits reflect the combined interactions of viruses and hosts; that is, they are not encoded solely by viral genomes. Viral life history traits can also vary by orders of magnitude, whether for time to lysis, burst size, probability of lysogeny, rate of induction, adsorption rate, or mortality rate.

scholarly journals Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

2015 ◽  
Vol 112 (7) ◽  
pp. 2034-2039 ◽  
Author(s):  
Xiancheng Zeng ◽  
Suchetana Mukhopadhyay ◽  
Charles L. Brooks
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Viral Entry ◽  
Drug Targets ◽  
Viral Infections ◽  
Driving Forces ◽  
Specific Treatment ◽  
Icosahedral Symmetry ◽  
Endosomal Membranes ◽  
Ph Dependent

Alphavirus envelope proteins, organized as trimers of E2–E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.

scholarly journals Drugs, Metabolites, and Lung Accumulating Small Lysosomotropic Molecules: Multiple Targeting Impedes SARS-CoV-2 Infection and Progress to COVID-19

2021 ◽  
Vol 22 (4) ◽  
pp. 1797
Author(s):  
Markus Blaess ◽  
Lars Kaiser ◽  
Oliver Sommerfeld ◽  
René Csuk ◽  
Hans-Peter Deigner
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
Second Messengers ◽  
Cathepsin L ◽  
Host Cells ◽  
Active Metabolites ◽  
Eligibility Criteria ◽  
Pulmonary Tissue ◽  
Over The Counter ◽  
Approved Drugs

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.

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