Pyronaridine tetraphosphate efficacy against Ebola virus infection in guinea pig.
The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 μM against three strains of EBOV and IC50 range of 1.01-2.72 μM against two strains of Marburg virus (MARV)) which is an approved drug in the European Union and used in combination with artesunate. To date, no small molecule drugs have shown statistically significant efficacy in the guinea pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs directed us to a single 300 mg/kg or 600 mg/kg oral dose of pyronaridine 1hr after infection. Pyronaridine resulted in statistically significant survival of 40% at 300 mg/kg and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 mg/kg dosed once a day) had 43.5% survival. All animals in the vehicle treatment group succumbed to disease by study day 12 (100% mortality). The in vitro metabolism and metabolite identification of pyronaridine and another of our EBOV active molecules, tilorone, suggested significant species differences which may account for the efficacy or lack thereof, respectively in guinea pig. In summary, our studies with pyronaridine demonstrates its utility for repurposing as an antiviral against EBOV and MARV.
['Lane|Thomas R|TR|', 'Massey|Christopher|C|', 'Comer|Jason E|JE|', 'Freiberg|Alexander N|AN|', 'Zhou|Huanying|H|', 'Dyall|Julie|J|', 'Holbrook|Michael R|MR|', 'Anantpadma|Manu|M|', 'Davey|Robert A|RA|', 'Madrid|Peter B|PB|', 'Ekins|Sean|S|']
D000818:Animals D000998:Antiviral Agents D004195:Disease Models, Animal D058492:Drug Repositioning D029043:Ebolavirus D005260:Female D006168:Guinea Pigs D019142:Hemorrhagic Fever, Ebola D006801:Humans D020128:Inhibitory Concentration 50 D008297:Male D029024:Marburgvirus D051379:Mice D008861:Microsomes D009287:Naphthyridines
Pyronaridine Guinea Pig Favipiravir Antiviral Ebola virus disease