Therapeutic development by repurposing drugs targeting SARS-CoV-2 spike protein interactions by simulation studies

There is no effective therapeutic or vaccine for Middle East Respiratory Syndrome and this study attempts to find therapy using peptide by establishing a basis for the peptide-protein interactions through in silico docking studies for the spike protein of MERS-CoV. The antimicrobial peptides (AMPs) were retrieved from the antimicrobial peptide database (APD3) and shortlisted based on certain important physicochemical properties. The binding mode of the shortlisted peptides was measured based on the number of clusters which forms in a protein-peptide docking using Piper. As a result, we identified a list of putative AMPs which binds to the spike protein of MERS-CoV, which may be crucial in providing the inhibitory action. It is observed that seven putative peptides have good binding score based on cluster size cutoff of 208. We conclude that seven peptides, namely, AP00225, AP00180, AP00549, AP00744, AP00729, AP00764, and AP00223, could possibly have binding with the active site of the MERS-CoV spike protein. These seven AMPs could serve as a therapeutic option for MERS and enhance its treatment outcome.

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The Dark Kinase Knowledgebase: an online compendium of knowledge and experimental results of understudied kinases

Nucleic Acids Research ◽

10.1093/nar/gkaa853 ◽

2020 ◽

Vol 49 (D1) ◽

pp. D529-D535 ◽

Cited By ~ 1

Author(s):

Matthew E Berginski ◽

Nienke Moret ◽

Changchang Liu ◽

Dennis Goldfarb ◽

Peter K Sorger ◽

...

Keyword(s):

Protein Interactions ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Knowledge Generation ◽

Data Resource ◽

Functional Relationships ◽

External Data ◽

Level Data ◽

Numerous Cell ◽

Therapeutic Development

Abstract Kinases form the backbone of numerous cell signaling pathways, with their dysfunction similarly implicated in multiple pathologies. Further facilitated by their druggability, kinases are a major focus of therapeutic development efforts in diseases such as cancer, infectious disease and autoimmune disorders. While their importance is clear, the role or biological function of nearly one-third of kinases is largely unknown. Here, we describe a data resource, the Dark Kinase Knowledgebase (DKK; https://darkkinome.org), that is specifically focused on providing data and reagents for these understudied kinases to the broader research community. Supported through NIH’s Illuminating the Druggable Genome (IDG) Program, the DKK is focused on data and knowledge generation for 162 poorly studied or ‘dark’ kinases. Types of data provided through the DKK include parallel reaction monitoring (PRM) peptides for quantitative proteomics, protein interactions, NanoBRET reagents, and kinase-specific compounds. Higher-level data is similarly being generated and consolidated such as tissue gene expression profiles and, longer-term, functional relationships derived through perturbation studies. Associated web tools that help investigators interrogate both internal and external data are also provided through the site. As an evolving resource, the DKK seeks to continually support and enhance knowledge on these potentially high-impact druggable targets.

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Neutral evolution test of the spike protein of SARS-CoV-2 and its implications in the binding to ACE2

Scientific Reports ◽

10.1038/s41598-021-96950-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Georgina I. López-Cortés ◽

Miryam Palacios-Pérez ◽

Gabriel S. Zamudio ◽

Hannya F. Veledíaz ◽

Enrique Ortega ◽

...

Keyword(s):

Protein Interactions ◽

Neutral Theory ◽

Purifying Selection ◽

Spike Protein ◽

Health Concern ◽

Neutral Evolution ◽

Evolutionary Mechanisms ◽

Theory Of Evolution ◽

Selective Pressures

AbstractAs the SARS-CoV-2 has spread and the pandemic has dragged on, the virus continued to evolve rapidly resulting in the emergence of new highly transmissible variants that can be of public health concern. The evolutionary mechanisms that drove this rapid diversity are not well understood but neutral evolution should open the first insight. The neutral theory of evolution states that most mutations in the nucleic acid sequences are random and they can be fixed or disappear by purifying selection. Herein, we performed a neutrality test to better understand the selective pressures exerted over SARS-CoV-2 spike protein from homologue proteins of Betacoronavirus, as well as to the spikes from human clinical isolates of the virus. Specifically, Tyr and Asn have higher occurrence rates on the Receptor Binding Domain (RBD) and in the overall sequence of spike proteins of Betacoronavirus, whereas His and Arg have lower occurrence rates. The in vivo evolutionary phenomenon of SARS-CoV-2 shows that Glu, Lys, Phe, and Val have the highest probability of occurrence in the emergent viral particles. Amino acids that have higher occurrence than the expected by the neutral control, are favorable and are fixed in the sequence while the ones that have lower occurrence than expected, influence the stability and/or functionality of the protein. Our results show that most unique mutations either for SARS-CoV-2 or its variants of health concern are under selective pressures, which could be related either to the evasion of the immune system, increasing the virus’ fitness or altering protein – protein interactions with host proteins. We explored the consequences of those selected mutations in the structure and protein – protein interaction with the receptor. Altogether all these forces have shaped the spike protein and the continually evolving variants.

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

10.1101/2021.05.08.443275 ◽

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.

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Insights on cross-species transmission of SARS-CoV-2 from structural modeling

10.1101/2020.06.05.136861 ◽

2020 ◽

Cited By ~ 6

Author(s):

João PGLM Rodrigues ◽

Susana Barrera-Vilarmau ◽

João MC Teixeira ◽

Elizabeth Seckel ◽

Panagiotis Kastritis ◽

...

Keyword(s):

Amino Acid ◽

Severe Acute Respiratory Syndrome ◽

Protein Interactions ◽

Animal Species ◽

Host Protein ◽

Spike Protein ◽

Computational Studies ◽

Wild Animals ◽

Amino Acid Residues ◽

Global Pandemic

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 14 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic, the question emerges whether human-to-animal transmission is possible and if so, which animal species are most at risk. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.

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Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development

Virus Research ◽

10.1016/j.virusres.2020.198141 ◽

2020 ◽

Vol 288 ◽

pp. 198141 ◽

Cited By ~ 7

Author(s):

Subodh Kumar Samrat ◽

Anil M. Tharappel ◽

Zhong Li ◽

Hongmin Li

Keyword(s):

Potential Role ◽

Spike Protein ◽

Therapeutic Development

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Identification of a Potent Inhibitor Targeting the Spike Protein of Pandemic Human Coronavirus, SARS-CoV-2 by Computational Methods

10.26434/chemrxiv.12197934.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

SRUTHI UNNI ◽

Snehal Aouti ◽

Padmanabhan Balasundaram

Keyword(s):

Vaccine Development ◽

Protein S ◽

Dynamics Simulation ◽

Spike Protein ◽

Simulation Studies ◽

Viral Pathogen ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Chemical Libraries ◽

Pi Interactions

<p>Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein – ACE2 interface by making substantial pi-pi interactions with Tyr505 in the ‘Site 1’ hook region of RBD and hydrophilic interactions with Glu406, Ser494 and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a potent repurpose drug to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.</p>

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Identification of a Potent Inhibitor Targeting the Spike Protein of Pandemic Human Coronavirus, SARS-CoV-2 by Computational Methods

10.26434/chemrxiv.12197934 ◽

2020 ◽

Author(s):

SRUTHI UNNI ◽

Snehal Aouti ◽

Padmanabhan Balasundaram

Keyword(s):

Vaccine Development ◽

Protein S ◽

Dynamics Simulation ◽

Spike Protein ◽

Simulation Studies ◽

Viral Pathogen ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Chemical Libraries ◽

Pi Interactions

<p>Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein – ACE2 interface by making substantial pi-pi interactions with Tyr505 in the ‘Site 1’ hook region of RBD and hydrophilic interactions with Glu406, Ser494 and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a potent repurpose drug to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.</p>

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β - catenin is central to DUX4 -driven network rewiring in facioscapulohumeral muscular dystrophy

Journal of The Royal Society Interface ◽

10.1098/rsif.2014.0797 ◽

2015 ◽

Vol 12 (102) ◽

pp. 20140797 ◽

Cited By ~ 19

Author(s):

Christopher R. S. Banerji ◽

Paul Knopp ◽

Louise A. Moyle ◽

Simone Severini ◽

Richard W. Orrell ◽

...

Keyword(s):

Gene Expression ◽

Muscular Dystrophy ◽

Protein Interactions ◽

Molecular Model ◽

Meta Analysis ◽

Facioscapulohumeral Muscular Dystrophy ◽

Aberrant Expression ◽

Incurable Disease ◽

Therapeutic Development ◽

Network Rewiring

Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring ( InSpiRe ), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe , we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4 , gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development.

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