scholarly journals Identification of viral-mediated pathogenic mechanisms in neurodegenerative diseases using network-based approaches

2020 ◽  
Author(s):  
Anna Onisiforou ◽  
George M. Spyrou
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Interactions ◽  
Symptomatic Relief ◽  
Critical Role ◽  
Unmet Need ◽  
Host Protein ◽  
Human Interactome ◽  
Pathogenic Mechanisms ◽  
Host Immune Responses ◽  
Kegg Pathways

AbstractDuring the course of a viral infection, virus-host protein-protein interactions (PPIs) play a critical role in allowing viruses to evade host immune responses, replicate and hence survive within the host. These interspecies molecular interactions can lead to viral-mediated perturbations of the human interactome causing the generation of various complex diseases, from cancer to neurodegenerative diseases (NDs). There are evidences suggesting that viral-mediated perturbations are a possible pathogenic aetiology in several NDs such as Amyloid Later Sclerosis, Parkinson’s disease, Alzheimer’s disease and Multiple Sclerosis (MS), as they can cause degeneration of neurons via both direct and/or indirect actions. These diseases share several common pathological mechanisms, as well as unique disease mechanisms that reflect disease phenotype. NDs are chronic degenerative diseases of the central nervous system and current therapeutic approaches provide only mild symptomatic relief rather than treating the disease at heart, therefore there is unmet need for the discovery of novel therapeutic targets and pharmacotherapies. In this paper we initially review databases and tools that can be utilized to investigate viral-mediated perturbations in complex NDs using network-based analysis by examining the interaction between the ND-related PPI disease networks and the virus-host PPI network. Afterwards we present our integrative network-based bioinformatics approach that accounts for pathogen-genes-disease related PPIs with the aim to identify viral-mediated pathogenic mechanisms focusing in MS disease. We identified 7 high centrality nodes that can act as disease communicator nodes and exert systemic effects in the MS enriched KEGG pathways network. In addition, we identified 12 KEGG pathways targeted by 67 viral proteins from 8 viral species that might exert viral-mediated pathogenic mechanisms in MS by interacting with the disease communicator nodes. Finally, our analysis highlighted the Th17 differentiation pathway, a hub-bottleneck disease communicator node and part of the 12 underlined KEGG pathways, as a key viral-mediated pathogenic mechanism and a possible therapeutic target for MS disease.

scholarly journals A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19

2020 ◽  
Author(s):  
Yadi Zhou ◽  
Yuan Hou ◽  
Jiayu Shen ◽  
Asha Kalianpur ◽  
Joe Zein ◽  
...  
Keyword(s):  
Single Cell ◽  
Protein Interactions ◽  
Drug Repurposing ◽  
Host Protein ◽  
Network Medicine ◽  
Angiotensin Ii Receptor ◽  
Sequencing Data ◽  
Human Interactome ◽  
Converting Enzyme Inhibitors ◽  
Test Result

The global Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of co-existing medical conditions while the underlying mechanisms remain unclear. Furthermore, there are no proven effective therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, diseases manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measure revealed underlying pathogenesis for broad COVID-19-associated manifestations. Multi-modal analyses of single-cell RNA-sequencing data showed that co-expression of <i>ACE2 </i>and <i>TMPRSS2 </i>was elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn's disease patients compared to uninflamed tissues, revealing shared pathobiology by COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicated that COVID-19 shared intermediate inflammatory endophenotypes with asthma (including<i>IRAK3</i> and <i>ADRB2</i>). To prioritize potential treatment, we combined network-based prediction and propensity score (PS) matching observational study of 18,118 patients from a COVID-19 registry. We identified that melatonin (odds ratio (OR) = 0.36, 95% confidence interval (CI) 0.22-0.59) was associated with 64% reduced likelihood of a positive laboratory test result for SARS-CoV-2. Using PS-matching user active comparator design, melatonin was associated with 54% reduced likelihood of SARS-CoV-2 positive test result compared to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (OR = 0.46, 95% CI 0.24-0.86).

scholarly journals Distinct Molecular Mechanisms of Host Immune Response Modulation by Arenavirus NP and Z Proteins

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 784
Author(s):  
Robert J. Stott ◽  
Thomas Strecker ◽  
Toshana L. Foster
Keyword(s):  
Immune Responses ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Significant Risk ◽  
Host Protein ◽  
Response Modulation ◽  
Species Barrier ◽  
African Countries ◽  
Host Immune Responses ◽  
Cellular Pathways

Endemic to West Africa and South America, mammalian arenaviruses can cross the species barrier from their natural rodent hosts to humans, resulting in illnesses ranging from mild flu-like syndromes to severe and fatal haemorrhagic zoonoses. The increased frequency of outbreaks and associated high fatality rates of the most prevalent arenavirus, Lassa, in West African countries, highlights the significant risk to public health and to the socio-economic development of affected countries. The devastating impact of these viruses is further exacerbated by the lack of approved vaccines and effective treatments. Differential immune responses to arenavirus infections that can lead to either clearance or rapid, widespread and uncontrolled viral dissemination are modulated by the arenavirus multifunctional proteins, NP and Z. These two proteins control the antiviral response to infection by targeting multiple cellular pathways; and thus, represent attractive targets for antiviral development to counteract infection. The interplay between the host immune responses and viral replication is a key determinant of virus pathogenicity and disease outcome. In this review, we examine the current understanding of host immune defenses against arenavirus infections and summarise the host protein interactions of NP and Z and the mechanisms that govern immune evasion strategies.

scholarly journals Different Subtypes of Influenza Viruses Target Different Human Proteins and Pathways Leading to Different Pathogenic Phenotypes

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Yujie Wang ◽  
Ting Song ◽  
Kaiwu Li ◽  
Yuan Jin ◽  
Junjie Yue ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Viral Proteins ◽  
Influenza Viruses ◽  
Host Protein ◽  
Protein Protein Interactions ◽  
Influenza A Viruses ◽  
Host Proteins ◽  
Pathogenic Mechanisms ◽  
Human Proteins

Different subtypes of influenza A viruses (IAVs) cause different pathogenic phenotypes after infecting human bodies. Analysis of the interactions between viral proteins and the host proteins may provide insights into the pathogenic mechanisms of the virus. In this paper, we found that the same proteins (nucleoprotein and neuraminidase) of H1N1 and H5N1 have different impacts on the NF-κB activation. By further examining the virus–host protein–protein interactions, we found that both NP and NA proteins of the H1N1 and H5N1 viruses target different host proteins. These results indicate that different subtypes of influenza viruses target different human proteins and pathways leading to different pathogenic phenotypes.

scholarly journals A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19

2020 ◽  
Author(s):  
Yadi Zhou ◽  
Yuan Hou ◽  
Jiayu Shen ◽  
Asha Kalianpur ◽  
Joe Zein ◽  
...  
Keyword(s):  
Single Cell ◽  
Protein Interactions ◽  
Drug Repurposing ◽  
Host Protein ◽  
Network Medicine ◽  
Angiotensin Ii Receptor ◽  
Sequencing Data ◽  
Human Interactome ◽  
Converting Enzyme Inhibitors ◽  
Test Result

The global Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of co-existing medical conditions while the underlying mechanisms remain unclear. Furthermore, there are no proven effective therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, diseases manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measure revealed underlying pathogenesis for broad COVID-19-associated manifestations. Multi-modal analyses of single-cell RNA-sequencing data showed that co-expression of <i>ACE2 </i>and <i>TMPRSS2 </i>was elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn's disease patients compared to uninflamed tissues, revealing shared pathobiology by COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicated that COVID-19 shared intermediate inflammatory endophenotypes with asthma (including<i>IRAK3</i> and <i>ADRB2</i>). To prioritize potential treatment, we combined network-based prediction and propensity score (PS) matching observational study of 18,118 patients from a COVID-19 registry. We identified that melatonin (odds ratio (OR) = 0.36, 95% confidence interval (CI) 0.22-0.59) was associated with 64% reduced likelihood of a positive laboratory test result for SARS-CoV-2. Using PS-matching user active comparator design, melatonin was associated with 54% reduced likelihood of SARS-CoV-2 positive test result compared to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (OR = 0.46, 95% CI 0.24-0.86).

Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

2019 ◽  
Vol 19 (6) ◽  
pp. 430-448 ◽  
Author(s):  
Khalid Bashir Dar ◽  
Aashiq Hussain Bhat ◽  
Shajrul Amin ◽  
Syed Anjum ◽  
Bilal Ahmad Reshi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Critical Role ◽  
Cancer Therapeutics ◽  
Adaptor Proteins ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Beta Catenin ◽  
Protein Protein Interactions ◽  
Apoptosis Protein

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

scholarly journals Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 767
Author(s):  
Priscila Baltazar Gonçalves ◽  
Ana Carolina Rennó Sodero ◽  
Yraima Cordeiro
Keyword(s):  
Drug Discovery ◽  
Neurodegenerative Diseases ◽  
Green Tea ◽  
Protein Misfolding ◽  
Financial Burden ◽  
Scientific Evidence ◽  
Symptomatic Relief ◽  
Public Health Problem ◽  
Bioactive Compound ◽  
Common Cause

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer’s disease (AD), and α-synuclein, linked to Parkinson’s disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

scholarly journals Native Structure-Based Peptides as Potential Protein–Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2157
Author(s):  
Norbert Odolczyk ◽  
Ewa Marzec ◽  
Maria Winiewska-Szajewska ◽  
Jarosław Poznański ◽  
Piotr Zielenkiewicz
Keyword(s):  
Drug Development ◽  
Protein Interactions ◽  
Rna Virus ◽  
Antiviral Drug ◽  
Host Protein ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Short Peptides ◽  
Virus Protein ◽  
Positive Strand Rna

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a positive-strand RNA virus that causes severe respiratory syndrome in humans, which is now referred to as coronavirus disease 2019 (COVID-19). Since December 2019, the new pathogen has rapidly spread globally, with over 65 million cases reported to the beginning of December 2020, including over 1.5 million deaths. Unfortunately, currently, there is no specific and effective treatment for COVID-19. As SARS-CoV-2 relies on its spike proteins (S) to bind to a host cell-surface receptor angiotensin-converting enzyme-2(ACE2), and this interaction is proved to be responsible for entering a virus into host cells, it makes an ideal target for antiviral drug development. In this work, we design three very short peptides based on the ACE2 sequence/structure fragments, which may effectively bind to the receptor-binding domain (RBD) of S protein and may, in turn, disrupt the important virus-host protein–protein interactions, blocking early steps of SARS-CoV-2 infection. Two of our peptides bind to virus protein with affinity in nanomolar range, and as very short peptides have great potential for drug development.

scholarly journals Coiled-coil networking shapes cell molecular machinery

2012 ◽  
Vol 23 (19) ◽  
pp. 3911-3922 ◽  
Author(s):  
Yongqiang Wang ◽  
Xinlei Zhang ◽  
Hong Zhang ◽  
Yi Lu ◽  
Haolong Huang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Critical Role ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Protein Protein Interactions ◽  
Full Spectrum ◽  
Kinetochore Assembly ◽  
Genome Wide ◽  
Molecular Machinery ◽  
Systematic Understanding

The highly abundant α-helical coiled-coil motif not only mediates crucial protein–protein interactions in the cell but is also an attractive scaffold in synthetic biology and material science and a potential target for disease intervention. Therefore a systematic understanding of the coiled-coil interactions (CCIs) at the organismal level would help unravel the full spectrum of the biological function of this interaction motif and facilitate its application in therapeutics. We report the first identified genome-wide CCI network in Saccharomyces cerevisiae, which consists of 3495 pair-wise interactions among 598 predicted coiled-coil regions. Computational analysis revealed that the CCI network is specifically and functionally organized and extensively involved in the organization of cell machinery. We further show that CCIs play a critical role in the assembly of the kinetochore, and disruption of the CCI network leads to defects in kinetochore assembly and cell division. The CCI network identified in this study is a valuable resource for systematic characterization of coiled coils in the shaping and regulation of a host of cellular machineries and provides a basis for the utilization of coiled coils as domain-based probes for network perturbation and pharmacological applications.

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