An orally available, small-molecule interferon inhibits viral replication

被引：39

作者：

Konishi, Hideyuki ^{[1
]}

Okamoto, Koichi ^{[1
]}

Ohmori, Yusuke ^{[1
]}

Yoshino, Hitoshi ^{[2
]}

Ohmori, Hiroshi ^{[1
]}

Ashihara, Motooki ^{[1
]}

Hirata, Yuichi ^{[3
]}

Ohta, Atsunori ^{[1
]}

Sakamoto, Hiroshi ^{[1
]}

Hada, Natsuko ^{[1
]}

Katsume, Asao ^{[1
]}

Kohara, Michinori ^{[3
]}

Morikawa, Kazumi ^{[2
]}

Tsukuda, Takuo ^{[1
]}

Shimma, Nobuo ^{[1
]}

Foster, Graham R. ^{[4
]}

Alazawi, William ^{[4
]}

Aoki, Yuko ^{[1
]}

Arisawa, Mikio ^{[1
]}

Sudoh, Masayuki ^{[1
]}

机构：

[1] Chugai Pharmaceut Co Ltd, Kamakura Res Labs, Kamakura, Kanagawa, Japan

[2] Chugai Pharmaceut Co Ltd, Fuji Gotemba Res Labs, Gotemba, Shizuoka, Japan

[3] Tokyo Metropolitan Inst Med Sci, Dept Microbiol & Cell Biol, Setagaya Ku, Tokyo 113, Japan

[4] Queen Mary Univ London, Blizard Inst Cellular & Mol Sci, London E1 4AT, England

来源：

SCIENTIFIC REPORTS | 2012年 / 2卷

关键词：

HEPATITIS-C VIRUS; TOLL-LIKE RECEPTOR; GENETIC-VARIATION; ALPHA-INTERFERON; CELLS; BETA; MICE; TELAPREVIR; RIBAVIRIN; STAT2;

D O I：

10.1038/srep00259

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Most acute hepatitis C virus (HCV) infections become chronic and some progress to liver cirrhosis or hepatocellular carcinoma. Standard therapy involves an interferon (IFN)-alpha-based regimen, and efficacy of therapy has been significantly improved by the development of protease inhibitors. However, several issues remain concerning the injectable form and the side effects of IFN. Here, we report an orally available, small-molecule type I IFN receptor agonist that directly transduces the IFN signal cascade and stimulates antiviral gene expression. Like type I IFN, the small-molecule compound induces IFN-stimulated gene (ISG) expression for antiviral activity in vitro and in vivo in mice, and the ISG induction mechanism is attributed to a direct interaction between the compound and IFN-alpha receptor 2, a key molecule of IFN-signaling on the cell surface. Our study highlights the importance of an orally active IFN-like agent, both as a therapy for antiviral infections and as a potential IFN substitute.

引用

页数：9

共 50 条

[31] Discovery of an Orally Active Small-Molecule Tumor Necrosis Factor-α Inhibitor
Sun, Weiguang
Wu, Yanli
Zheng, Mengzhu
Yang, Yueying
Liu, Yang
Wu, Canrong
Zhou, Yirong
Zhang, Yonghui
Chen, Lixia
Li, Hua
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (15) : 8146 - 8156
[32] Design of orally bioavailable proteolysis targeting chimera (PROTAC) small-molecule degraders
Wang, Shaomeng
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2019, 258
[33] Synthesis of orally active small-molecule gonadotropin-releasing hormone antagonists
Tucci, FC
Chen, C
CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT, 2004, 7 (06) : 832 - 847
[34] H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers
Seiler, Michael
Yoshimi, Akihide
Darman, Rachel
Chan, Betty
Keaney, Gregg
Thomas, Michael
Agrawal, Anant A.
Caleb, Benjamin
Csibi, Alfredo
Sean, Eckley
Fekkes, Peter
Karr, Craig
Klimek, Virginia
Lai, George
Lee, Linda
Kumar, Pavan
Lee, Stanley Chun-Wei
Liu, Xiang
Mackenzie, Crystal
Meeske, Carol
Mizui, Yoshiharu
Padron, Eric
Park, Eunice
Pazolli, Ermira
Peng, Shouyong
Prajapati, Sudeep
Taylor, Justin
Teng, Teng
Wang, John
Warmuth, Markus
Yao, Huilan
Yu, Lihua
Zhu, Ping
Abdel-Wahab, Omar
Smith, Peter G.
Buonamici, Silvia
NATURE MEDICINE, 2018, 24 (04) : 497 - +
[35] Identification and characterization of novel small-molecule inhibitors of the replication checkpoint.
Bradner, J
Kim, YS
Koehler, A
Kawasumi, M
Li, XD
Schreiber, SL
Nghiem, P
BLOOD, 2004, 104 (11) : 218A - 218A
[36] Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication
Thenin-Houssier, Suzie
de Vera, Ian Mitchelle S.
Pedro-Rosa, Laura
Brady, Angela
Richard, Audrey
Konnick, Briana
Opp, Silvana
Buffone, Cindy
Fuhrmann, Jakob
Kota, Smitha
Billack, Blase
Pietka-Ottlik, Magdalena
Tellinghuisen, Timothy
Choe, Hyeryun
Spicer, Timothy
Scampavia, Louis
Diaz-Griffero, Felipe
Kojetin, Douglas J.
Valente, Susana T.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2016, 60 (04) : 2195 - 2208
[37] A Small-Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity
Massignan, Tania
Sangiovanni, Valeria
Biggi, Silvia
Stincardini, Claudia
Elezgarai, Saioa R.
Maietta, Giulia
Andreev, Ivan A.
Ratmanova, Nina K.
Belov, Dmitry S.
Lukyanenko, Evgeny R.
Belov, Grigory M.
Barreca, Maria Letizia
Altieri, Andrea
Kurkin, Alexander V.
Biasini, Emiliano
CHEMMEDCHEM, 2017, 12 (16) : 1286 - 1292
[38] Bleomycin is a potent small-molecule inhibitor of hepatitis C virus replication
Rakic, Bojana
Brulotte, Marc
Rouleau, Yanouchka
Belanger, Sylvie
Pezacki, John Paul
CHEMBIOCHEM, 2006, 7 (09) : 1330 - 1333
[39] Targeting PKC in multiple myeloma:: In vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCI).
Raab, Marc S.
Podar, Klaus
Zhang, Jing
McMillin, Douglas
Breitkreutz, Iris
Tai, Yu-Tzu
Lin, Boris
Ghobrial, Irene
Munshi, Nikhil
Hideshima, Teru
Chauhan, Dharminder
Anderson, Kenneth C.
BLOOD, 2006, 108 (11) : 989A - 989A
[40] Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl)
Podar, Klaus
Raab, Marc S.
Zhang, Jing
McMillin, Douglas
Breitkreutz, Iris
Tai, Yu-Tzu
Lin, Boris K.
Munshi, Nikhil
Hideshima, Teru
Chauhan, Dharminder
Anderson, Kenneth C.
BLOOD, 2007, 109 (04) : 1669 - 1677

← 1 2 3 4 5 →