title: A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation.
abstract: Respiratory syncytial virus (RSV) and influenza A virus are leading causes of acute lower respiratory infectious disease. Respiratory diseases caused by RSV and influenza A virus result in serious economic burden and life-threatening disease for immunocompromised people. With the revelation that p38 mitogen-activated protein kinase (MAPK) activity in host cells is crucial for infection and replication of RSV and influenza A virus, inhibition of p38 MAPK activity has been suggested as a potential antiviral therapeutic strategy. However, the low selectivity and high toxicity of the p38 MAPK inhibitors necessitate the development of better inhibitors. Herein, we report the synthesis of a novel p38 MAPK inhibitor, NJK14047, with high kinase selectivity. In this work, it was demonstrated that NJK14047 inhibits RSV- and influenza A-mediated p38 MAPK activation in epithelial cells. Subsequently, NJK14047 treatment resulted in decreased viral replication and viral mRNA synthesis. In addition, secretion of interleukin-6 from infected cells was greatly diminished by NJK14047, suggesting that it can ameliorate immunopathological responses to RSV and influenza A. Collectively, the results suggest that NJK14047 has therapeutic potential to treat respiratory viral infection through the suppression of p38 MAPK activation, which is suggested to be an essential step for respiratory virus infection.
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Myung-Soo
authors.initials: MS
authors.lastname: Choi
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Jinyuk
authors.initials: J
authors.lastname: Heo
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Chae-Min
authors.initials: CM
authors.lastname: Yi
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Junsu
authors.initials: J
authors.lastname: Ban
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Noh-Jin
authors.initials: NJ
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Na-Rae
authors.initials: NR
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: kimnj@khu.ac.kr.
authors.forename: Nam-Jung
authors.initials: NJ
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: innks@khu.ac.kr.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Inn
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D012367:RNA, Viral; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Antiviral agent; Influenza A virus; Respiratory syncytial virus; p38 mitogen activated protein kinase