SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

2020 ◽  
Author(s):  
Lucas Prescott
Keyword(s):  
Drug Targets ◽  
Human Proteome ◽  
Host Protein ◽  
Nuclear Condensation ◽  
Viral Proteases ◽  
Nascent Chain ◽  
Human Proteins ◽  
Immune Tissues ◽  
Cellular Pathways ◽  
Novel Coronavirus

AbstractA novel coronavirus (SARS-CoV-2) has devastated the globe as a pandemic that has killed more than 1,600,000 people. Widespread vaccination is still uncertain, so many scientific efforts have been directed toward discovering antiviral treatments. Many drugs are being investigated to inhibit the coronavirus main protease, 3CLpro, from cleaving its viral polyprotein, but few publications have addressed this protease’s interactions with the host proteome or their probable contribution to virulence. Too few host protein cleavages have been experimentally verified to fully understand 3CLpro’s global effects on relevant cellular pathways and tissues. Here, I set out to determine this protease’s targets and corresponding potential drug targets. Using a neural network trained on cleavages from 388 coronavirus proteomes with a Matthews correlation coefficient of 0.983, I predict that a large proportion of the human proteome is vulnerable to 3CLpro, with 4,460 out of approximately 20,000 human proteins containing at least one putative cleavage site. These cleavages are nonrandomly distributed and are enriched in the epithelium along the respiratory tract, brain, testis, plasma, and immune tissues and depleted in olfactory and gustatory receptors despite the prevalence of anosmia and ageusia in COVID-19 patients. Affected cellular pathways include cytoskeleton/motor/cell adhesion proteins, nuclear condensation and other epigenetics, host transcription and RNAi, ribosomal stoichiometry and nascent-chain detection and degradation, coagulation, pattern recognition receptors, growth factors, lipoproteins, redox, ubiquitination, and apoptosis. This whole proteome cleavage prediction demonstrates the importance of 3CLpro in expected and nontrivial pathways affecting virulence, lead me to propose more than a dozen potential therapeutic targets against coronaviruses, and should therefore be applied to all viral proteases and subsequently experimentally verified.

scholarly journals A network biology approach for identifying crucial host targets for COVID-19

2020 ◽  
Author(s):  
Ranjan Kumar Barman ◽  
Anirban Mukhopadhyay ◽  
Ujjwal Maulik ◽  
Santasabuj Das
Keyword(s):  
Drug Targets ◽  
Rna Synthesis ◽  
Interaction Network ◽  
Drug Repurposing ◽  
Adenosine Monophosphate ◽  
Network Biology ◽  
Centrality Measures ◽  
Potential Candidate ◽  
Human Proteins ◽  
Novel Coronavirus

In late December 2019, an outbreak of novel coronavirus SARS-CoV-2 originated in Wuhan city of china, has infected over 30,00,000 people worldwide. SARS-CoV-2 is a causative agent of COVID-19 that has killed over 2,11,000 people and created social and financial crisis globally. Currently, there is no effective antiviral drugs and vaccine available for the prevention of COVID-19. Therefore, the scientific community is more focused on drug repurposing for the treatment of COVID-19. Here, we propose a network biology approach to identify candidate biomarkers for COVID-19. We critically analyze SARS-CoV-2 targeted human proteins and their interaction network. We utilize a combination of essential network centrality measures and functional properties of human proteins to find the critical human targets for SARS-CoV-2 infection. From the candidate pool of 301 human proteins, interestingly we found that PRKACA, RHOA, CDK5RAP2, and CEP250 are candidates for therapeutic targets for COVID-19. PRKACA and CEP250 have also been found by another group for potential candidates for drug targets in treating COVID-19. We found that potential candidate drugs/compounds such as guanosine triphosphate, remdesivir, adenosine monophosphate, MgATP, and H-89 dihydrochloride for COVID-19. Most of the therapeutics development studies for COVID-19 are tried to block RNA synthesis through RNA dependent RNA Polymerase (RdRP). Our findings also suggest for blocking RNA synthesis in treating COVID-19.

scholarly journals An Integrated Systems Biology Approach Identifies the Proteasome as a Critical Host Machinery for ZIKV and DENV Replication

2020 ◽  
Author(s):  
Guang Song ◽  
Emily M. Lee ◽  
Jianbo Pan ◽  
Miao Xu ◽  
Hee-Sool Rho ◽  
...  
Keyword(s):  
Systems Biology ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Protein Complexes ◽  
Proteasome Inhibitors ◽  
Host Protein ◽  
Disease Pathogenesis ◽  
Protein Protein Interaction ◽  
Cellular Pathways ◽  
Systematic Understanding

AbstractThe Zika (ZIKV) and dengue (DENV) flaviviruses exhibit similar replicative processes but distinct clinical outcomes. A systematic understanding of virus-host protein-protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes to identify host proteins required for ZIKV infection uncovered proteasome proteins. Third, a high-throughput screening of 6,016 bioactive compounds for ZIKV inhibitors yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoints proteasome as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus-host interactions, disease pathogenesis, and new drug targets.

scholarly journals A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

2020 ◽  
Author(s):  
David E. Gordon ◽  
Gwendolyn M. Jang ◽  
Mehdi Bouhaddou ◽  
Jiewei Xu ◽  
Kirsten Obernier ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Drug Targets ◽  
Affinity Purification ◽  
Drug Repurposing ◽  
Human Protein ◽  
Protein Protein Interaction ◽  
Human Proteins ◽  
Interaction Map ◽  
Novel Coronavirus ◽  
Approved Drugs

ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Vol 27 ◽  
Author(s):  
Sehrish Bano ◽  
Abdul Hameed ◽  
Mariya Al-Rashida ◽  
Shafia Iftikhar ◽  
Jamshed Iqbal
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Structural Features ◽  
Antiviral Drugs ◽  
Rna Dependent Rna Polymerase ◽  
Mortality And Morbidity ◽  
Functional Relationships ◽  
Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

scholarly journals A computational interactome and functional annotation for the human proteome

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
José Ignacio Garzón ◽  
Lei Deng ◽  
Diana Murray ◽  
Sagi Shapira ◽  
Donald Petrey ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Complexes ◽  
Enrichment Analysis ◽  
Human Proteome ◽  
Gene Set Enrichment Analysis ◽  
Protein Protein Interactions ◽  
Functional Relationships ◽  
Structural Relationships ◽  
Human Proteins ◽  
Validation Tests

We present a database, PrePPI (Predicting Protein-Protein Interactions), of more than 1.35 million predicted protein-protein interactions (PPIs). Of these at least 127,000 are expected to constitute direct physical interactions although the actual number may be much larger (~500,000). The current PrePPI, which contains predicted interactions for about 85% of the human proteome, is related to an earlier version but is based on additional sources of interaction evidence and is far larger in scope. The use of structural relationships allows PrePPI to infer numerous previously unreported interactions. PrePPI has been subjected to a series of validation tests including reproducing known interactions, recapitulating multi-protein complexes, analysis of disease associated SNPs, and identifying functional relationships between interacting proteins. We show, using Gene Set Enrichment Analysis (GSEA), that predicted interaction partners can be used to annotate a protein’s function. We provide annotations for most human proteins, including many annotated as having unknown function.

Insights into the Dynamic Fluctuations of the Protein HPV16 E1 and Identification of Motifs by Using Elastic Network Modeling

2021 ◽  
Vol 28 ◽  
Author(s):  
Rabbiah Malik ◽  
Sahar Fazal
Keyword(s):  
Drug Targets ◽  
Network Models ◽  
Hpv Infection ◽  
Elastic Network ◽  
Conserved Sequence ◽  
Linear Peptide ◽  
Peptide Motifs ◽  
E1 Protein ◽  
Human Proteins ◽  
Viral Helicase

Background: Cancers of cervix, head and neck regions have been found to be associated with Human Papilloma Virus (HPV) infection. E1 protein makes an important papillomavirus replication factor. Among the ORFs of papillomaviruses, the most conserved sequence is that of the E1 ORF. It is the viral helicase with being a member of class of ATPases associated with diverse cellular activities (AAA+) helicases. The interactions of E1 with human DNA and proteins occurs in the presence of short linear peptide motifs on E1 identical to those on human proteins. Methods: Different Motifs were identified on HPV16 E1 by using ELMs. Elastic network models were generated by using 3D structures of E1. Their dynamic fluctuations were analyzed on the basis of B factors, correlation analysis and deformation energies. Results: 3 motifs were identified on E1 which can interact with Cdk and Cyclin domains of human proteins. 11 motifs identified on E1 have their CDs of Pkinase on human proteins. LIG_MYND_2 has been identified as involved in stabilizing interaction of E1 with Hsp40 and Hsp70. These motifs and amino acids comprising these motifs play a major role in maintaining interactions with human proteins, ultimately causing infections leading to cancers. Conclusion: Our study identified various motifs on E1 which interact with specific counter domains found in human proteins, already reported having the interactions with E1. We also validated the involvement of these specific motifs containing regions of E1 by modeling elastic networks of E1. These motif involving interactions could be used as drug targets.

Scaffold Proteins and their Roles in Human Diseases

2020 ◽  
Vol 14 (01) ◽  
pp. 15-29
Author(s):  
Somsubhro Mukherjee ◽  
Boon Chuan Low
Keyword(s):  
Cell Signaling ◽  
Signaling Pathways ◽  
Drug Targets ◽  
Metabolic Diseases ◽  
Scaffold Proteins ◽  
Human Diseases ◽  
Normal Functions ◽  
Cellular Pathways ◽  
Cell Signaling Pathways

Scaffold proteins are critical regulators of important cell signaling pathways. Though scaffolds are not stringently defined in meaning, they are known to interact with numerous components of a signaling pathway, binding and bridging them into distinct and functional complexes. They control signal transduction and assist the localization of pathway components (organized in complexes) to definite regions of the cell such as the endosomes, plasma membrane, the cytoplasm, mitochondria, Golgi, and the nucleus. Years of research in this field have revealed the versatility of this class of protein and the important role it plays in maintaining the normal functions of the human body. Here, we discuss the role of several scaffold proteins which are implicated in important signaling pathways that play important roles in cardiac diseases, metabolic diseases, neurological disorders, and cancer. Their versatility and functions in human diseases make them attractive drug targets, several of which have been investigated in clinical trials. Future studies of scaffold proteins should give us an in-depth knowledge of how cell signaling works in normal and pathological conditions and would offer avenues to disrupt harmful cellular pathways to circumvent diseases.

PDID: Database of Experimental and Putative Drug Targets in Human Proteome

2019 ◽  
pp. 827-847 ◽  
Author(s):  
Chen Wang ◽  
Michal Brylinski ◽  
Lukasz Kurgan
Keyword(s):  
Drug Targets ◽  
Human Proteome

scholarly journals Bio- and Nanotechnology as the Key for Clinical Application of Salivary Peptide Histatin: A Necessary Advance

2020 ◽  
Vol 8 (7) ◽  
pp. 1024
Author(s):  
Carolina Reis Zambom ◽  
Fauller Henrique da Fonseca ◽  
Saulo Santesso Garrido
Keyword(s):  
Drug Targets ◽  
Extracellular Enzymes ◽  
Innate Immune ◽  
Host Protein ◽  
Histatin 5 ◽  
Salivary Peptide ◽  
Current Review ◽  
Adaptive Mechanisms ◽  
Antifungal Peptides ◽  
Near Future

Candida albicans is a common microorganism of human’s microbiota and can be easily found in both respiratory and gastrointestinal tracts as well as in the genitourinary tract. Approximately 30% of people will be infected by C. albicans during their lifetime. Due to its easy adaptation, this microorganism started to present high resistance to antifungal agents which is associated with their indiscriminate use. There are several reports of adaptive mechanisms that this species can present. Some of them are intrinsic alteration in drug targets, secretion of extracellular enzymes to promote host protein degradation and efflux receptors that lead to a diminished action of common antifungal and host’s innate immune response. The current review aims to bring promising alternatives for the treatment of candidiasis caused mainly by C. albicans. One of these alternatives is the use of antifungal peptides (AFPs) from the Histatin family, like histatin-5. Besides that, our focus is to show how nanotechnology can allow the application of these peptides for treatment of this microorganism. In addition, our intention is to show the importance of nanoparticles (NPs) for this purpose, which may be essential in the near future.

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