Dissertation/Thesis Abstract

Combining Protein Interactions and Functionality Classification in NS3 to Determine Specific Antiviral Targets in Dengue
by Alomair, Lamya, Ph.D., George Mason University, 2017, 124; 10279841
Abstract (Summary)

Dengue virus (DENV) is a serious worldwide health concern putting about 2.5 billion people in more than 100 countries at-risk Dengue is a member of the flaviviridae family, is transmitted to human via mosquitos. Dengue is a deadly viral disease. Unfortunately, there are no vaccines or antiviral that can prevent this infection and that is why researchers are diligently working to find cures. The DENV genome codes for multiple nonstructural proteins one of which is the NS3 enzyme that participates in different steps of the viral life cycle including viral replication, viral RNA genome synthesis and host immune mechanism. Recent studies suggest the role of fatty acid biogenesis during DENV infection, including posttranslational protein modification. Phosphorylation is among the protein post translational modifications and plays essential roles in protein folding, interactions, signal transduction, survival and apoptosis.

In silico study provides a powerful approach to gain a better understanding of the biological systems at the gene level. NS3 has the potential to be phosphorylated by any of the ∼500 human kinases. We predicted potential kinases that might phosphorylate NS3 and calculated Dena ranking score using neural network and other machine learning based webserver programs. These scores enabled us to investigate and identify the top kinases that phosphorylate DENV NS3. We hypothesize that preventing the phosphorylation of NS3 may interrupt the viral replication and participate in antiviral evasion. Using multiple sequence alignment bioinformatics tools we verified the results of the highly conserved residues and the residues around active sites whose phosphorylation may have a potential effect on viral replication. We further verified the results with multiple bioinformatics tools. Moreover, we included the Zika virus in our research and analysis taking into consideration the facts that Zika is related to the dengue virus because it belongs to the same Flavivirus genus affecting humans which might lead to a lot of similarities between Zika and Dengue, and that Zika is available for in vitro testing.

Our studies propose that the Host-Mediated Phosphorylation of NS3 would affect its capability to interact with NS5 and knocking out one of the interacting proteins may inhibit viral replication. These results will open new doors for further investigation and future work is expected to help identify the key inhibition mechanisms.

Indexing (document details)
Advisor: Jafri, Saleet M.
Commitee: Narayanan, Aarthi, Vaisman, Iosif
School: George Mason University
Department: Computational Science
School Location: United States -- Virginia
Source: DAI-B 79/01(E), Dissertation Abstracts International
Subjects: Bioinformatics
Keywords: Dengue, Flaviviridae, Kinase, Lamya alomair, Ns3, Zika
Publication Number: 10279841
ISBN: 978-0-355-30263-9
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