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dc.contributor.authorSvensmark, Julius
dc.date.accessioned2018-05-31T17:37:39Z
dc.date.available2018-05-31T17:37:39Z
dc.identifier.urihttp://hdl.handle.net/10898/5072
dc.description.abstractα-methylbenzyl thiourea compound is a novel inhibitor of the varicella-zoster virus (VZV), which is predicted to bind the virus’ portal protein, pORF54, hereby inhibiting the encapsidation process of the viral replication cycle. The open reading frame 54 (ORF54) gene encodes an 87 kDa monomer which oligomerizes to form the VZV pORF54 portal complex, which docks onto the viral capsid to facilitate the translocation of a newly synthesized VZV genome into the preformed empty capsid. Mutational mapping of compound resistant isolates has strongly suggested that the thiourea compound binds to and acts on the portal complex, though no specific binding pocket was revealed. In this thesis, we identify three particular resistant mutants, all of which have a substitution located in a putative wing/stem section of the portal monomer referred to as the ledge, and all unique in terms of the magnitude of resistance they confer. We hypothesize that the area where the three mutations are located makes up the compound binding pocket. Through a recombineering technique using bacterial artificial chromosomes (BAC) we were able to produce a set of VZV mutants, designed to reveal the chemical and physical importance of each of the three resistance mutations. We were able to describe a high level of sensitivity to any structural change at any of the three amino acid (AA) positions, where only the structurally most similar mutations led to retained sensitivity towards compound. The results demonstrate the possibility for this particular area of the protein acting as the compound binding pocket and allow us to more accurately predict a mechanism of action (MOA) in which α-methylbenzyl thiourea compound binds to the ledge of the portal complex and prevents insertion into the viral capsid.
dc.titleSTRUCTURAL ANALYSIS OF VZV PORTAL PROTEIN, pORF54, INTERACTION WITH ENCAPSIDATION INHIBITOR α-METHYLBENZYL THIOUREA COMPOUND
dc.date.updated2017-07-19T23:34:30Z
dc.language.rfc3066en


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