Identification of Common Biological Pathways and Drug Targets Across Multiple Respiratory Viruses Based on Human Host Gene Expression Analysis

Smith, Steven B.; Dampier, William; Tozeren, Aydin; Brown, James R.; Magid-Slav, Michal

We sought drug repurposing candidate targets from the top five enriched pathways and the Parkin-UPS pathway by searching the DrugBank database, version 3.0 (http://www.drugbank.ca/ accessed August 2011) [29] [30] [31] , for drugs targeting any of the 67 differentially expressed genes with a viral frequency of at least five (Table S6 ). Of these, thirteen genes, or almost 20% of the original 67 genes, were associated with at least one approved small molecule or protein therapy. There genes were: prostaglandinendoperoxide synthase 2 (PTGS2), TNF, matrix metallopeptidase 9 (MMP9), jun proto-oncogene (JUN), interleukin 1 beta (IL1B), CCL2, CD86, coagulation factor III (F3), phosphoinositide-3kinase regulatory subunit 1 (PIK3R1), intercellular adhesion molecule 1 (ICAM1), nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2), Caspase 1 (CASP1), and tubulin beta 3 (TUBB3). A selection of these genes, along with other characteristics to evaluate their potential as drug targets such as involvement in immune response [29] [30] [31] , Jackson Laboratory knock-in/knock-out mouse (JAX) phenotype [32] , approved or marketed small molecule drug or protein therapy, and current indications for that drug, are listed in Table 4 . Note that the current indication may not be for the gene target listed. Mimosine (gene target: CCL2) and Glucosamine (gene targets: NFKB2 and MMP9) did not have a current indication, while the interactions of Natalizumab (gene target: ICAM1) and Gallium nitrate (gene target: ILB1) with their gene targets were unclear. Additionally, therapies associated with PTGS2 are cyclooxygenase (COX-2) inhibitors which have known side-effect issues thus were not explored further. Therefore, NFKB2, ICAM1 and PTGS2 were excluded from Table 4 , leaving ten genes for potential drug repurposing. The potential cases for drug repurposing are discussed more in-depth for four targets; F3, IL1B, TNF and CASP1.