ChemMedChem p. 1953 - 1968 (2017)
Update date:2022-08-03
Topics:
Ivanova, Teodora
Hardes, Kornelia
Kallis, Stephanie
Dahms, Sven O.
Than, Manuel E.
Künzel, Sebastian
B?ttcher-Friebertsh?user, Eva
Lindberg, Iris
Jiao, Guan-Sheng
Bartenschlager, Ralf
Steinmetzer, Torsten
The proprotein convertase furin is a potential target for drug design, especially for the inhibition of furin-dependent virus replication. All effective synthetic furin inhibitors identified thus far are multibasic compounds; the highest potency was found for our previously developed inhibitor 4-(guanidinomethyl)phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148). An initial study in mice revealed a narrow therapeutic range for this tetrabasic compound, while significantly reduced toxicity was observed for some tribasic analogues. This suggests that the toxicity depends at least to some extent on the overall multibasic character of this inhibitor. Therefore, in a first approach, the C-terminal benzamidine of MI-1148 was replaced by less basic P1 residues. Despite decreased potency, a few compounds still inhibit furin in the low nanomolar range, but display negligible efficacy in cells. In a second approach, the P2 arginine was replaced by lysine; compared to MI-1148, this furin inhibitor has slightly decreased potency, but exhibits similar antiviral activity against West Nile and Dengue virus in cell culture and decreased toxicity in mice. These results provide a promising starting point for the development of efficacious and well-tolerated furin inhibitors.
View MoreShanghai Pengkai Chemical Co.,Ltd
Contact:+86-21-60526671
Address:No.4226 Duzhuang Rd Minhang District Shanghai China
Tianjin Realet Chemical Technology Co.,Ltd.
website:http://www.realetchem.com
Contact:+86-022-58788819
Address:shuanggang industrial park
GUANGZHOUGRENSPSPORTS FACILITIES CO LTD
Contact:
Address:
Hubei Xiangxi Chemical Industry Co.,Ltd
Contact:+86-710-3454830
Address:No.7, Daqing East Road, Xiangfan City, Hubei Province, China
Contact:+65 9658 0999
Address:26 Sin Ming Lane, Midview City, #05-118, Singapore 573971
Doi:10.1021/jo00307a015
(1990)Doi:10.1016/j.jorganchem.2010.01.011
(2010)Doi:10.1021/ma201610y
(2011)Doi:10.1021/jm980081y
(1998)Doi:10.1021/ja00199a033
(1989)Doi:10.3762/bjoc.8.125
(2012)