tetano
Editor, Senior Moderator
Science
. 2021 Jan 25;eabf4058.
doi: 10.1126/science.abf4058. Online ahead of print.
Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
Kris M White[SUP] #[/SUP][SUP] 1 2 [/SUP], Romel Rosales[SUP] #[/SUP][SUP] 3 2 [/SUP], Soner Yildiz[SUP] 3 2 [/SUP], Thomas Kehrer[SUP] 3 2 [/SUP], Lisa Miorin[SUP] 3 2 [/SUP], Elena Moreno[SUP] 3 2 [/SUP], Sonia Jangra[SUP] 3 2 [/SUP], Melissa B Uccellini[SUP] 3 2 [/SUP], Raveen Rathnasinghe[SUP] 3 2 [/SUP], Lynda Coughlan[SUP] 4 [/SUP], Carles Martinez-Romero[SUP] 3 2 [/SUP], Jyoti Batra[SUP] 5 6 7 8 [/SUP], Ajda Rojc[SUP] 5 6 7 8 [/SUP], Mehdi Bouhaddou[SUP] 5 6 7 8 [/SUP], Jacqueline M Fabius[SUP] 5 7 [/SUP], Kirsten Obernier[SUP] 5 6 7 8 [/SUP], Marion Dejosez[SUP] 9 [/SUP], Mar?a Jos? Guill?n[SUP] 10 [/SUP], Alejandro Losada[SUP] 10 [/SUP], Pablo Avil?s[SUP] 10 [/SUP], Michael Schotsaert[SUP] 3 2 [/SUP], Thomas Zwaka[SUP] 9 [/SUP], Marco Vignuzzi[SUP] 11 [/SUP], Kevan M Shokat[SUP] 5 7 8 12 [/SUP], Nevan J Krogan[SUP] 1 5 6 7 8 [/SUP], Adolfo Garc?a-Sastre[SUP] 1 2 13 14 [/SUP]
Affiliations
Abstract
SARS-CoV-2 viral proteins interact with the eukaryotic translation machinery and inhibitors of translation have potent antiviral effects. Here we report that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (IC[SUB]90[/SUB] = 0.88 nM) 27.5-fold more potent than remdesivir against SARS-CoV-2 in vitro, with limited toxicity in cell culture. Through the use of a drug resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A. We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
. 2021 Jan 25;eabf4058.
doi: 10.1126/science.abf4058. Online ahead of print.
Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
Kris M White[SUP] #[/SUP][SUP] 1 2 [/SUP], Romel Rosales[SUP] #[/SUP][SUP] 3 2 [/SUP], Soner Yildiz[SUP] 3 2 [/SUP], Thomas Kehrer[SUP] 3 2 [/SUP], Lisa Miorin[SUP] 3 2 [/SUP], Elena Moreno[SUP] 3 2 [/SUP], Sonia Jangra[SUP] 3 2 [/SUP], Melissa B Uccellini[SUP] 3 2 [/SUP], Raveen Rathnasinghe[SUP] 3 2 [/SUP], Lynda Coughlan[SUP] 4 [/SUP], Carles Martinez-Romero[SUP] 3 2 [/SUP], Jyoti Batra[SUP] 5 6 7 8 [/SUP], Ajda Rojc[SUP] 5 6 7 8 [/SUP], Mehdi Bouhaddou[SUP] 5 6 7 8 [/SUP], Jacqueline M Fabius[SUP] 5 7 [/SUP], Kirsten Obernier[SUP] 5 6 7 8 [/SUP], Marion Dejosez[SUP] 9 [/SUP], Mar?a Jos? Guill?n[SUP] 10 [/SUP], Alejandro Losada[SUP] 10 [/SUP], Pablo Avil?s[SUP] 10 [/SUP], Michael Schotsaert[SUP] 3 2 [/SUP], Thomas Zwaka[SUP] 9 [/SUP], Marco Vignuzzi[SUP] 11 [/SUP], Kevan M Shokat[SUP] 5 7 8 12 [/SUP], Nevan J Krogan[SUP] 1 5 6 7 8 [/SUP], Adolfo Garc?a-Sastre[SUP] 1 2 13 14 [/SUP]
Affiliations
- PMID: 33495306
- DOI: 10.1126/science.abf4058
Abstract
SARS-CoV-2 viral proteins interact with the eukaryotic translation machinery and inhibitors of translation have potent antiviral effects. Here we report that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (IC[SUB]90[/SUB] = 0.88 nM) 27.5-fold more potent than remdesivir against SARS-CoV-2 in vitro, with limited toxicity in cell culture. Through the use of a drug resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A. We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.