GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.
Bottom Line: The GRP78 inhibitor OSU-03012 (AR-12) interacted with sildenafil (Viagra) or tadalafil (Cialis) to rapidly reduce GRP78 levels in eukaryotes and as a single agent reduce Dna K levels in prokaryotes.Pre-treatment with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with it also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce.OSU-03012 as a single agent at clinically relevant concentrations killed laboratory generated antibiotic resistant E. coli and clinical isolate multi-drug resistant N. gonorrhoeae and MRSE which was in bacteria associated with reduced Dna K and Rec A expression.
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298.Show MeSH
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Mentions: OSU-03012 + sildenafil treatment rapidly decreased expression of the coxsakie and adenovirus receptor (CAR) in a dose- and time-dependent fashion that was modestly reduced by in a cell type dependent fashion by over-expression of GRP78 (Fig. 4A and B). Pre-treatment of cells with OSU-03012 + sildenafil significantly reduced the ability of a serotype 5 virus expressing GFP to infect cells and reduced the production of GFP when drug treatment occurred after virus infection (Fig. 4C–E). OSU-03012 + sildenafil treatment following virus infection also reduced the ability of a serotype 5 adenovirus to replicate as judged by infected cell killing. Pre-treatment of cells with OSU-03012 + sildenafil or OSU-03012 + sildenafil treatment following virus infection suppressed the ability of coxsakie B4 virus to kill infected cells 18 h after infection (Figure 4F). Over-expression of GRP78 enhanced the abilities of adenovirus and coxsakie virus to kill and abolished the protective effect of OSU-03012 + sildenafil treatment (Fig. 4G and H). Knock down of GRP78 also suppressed virus –induced killing (Fig. 4I and J).
Affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298.