tetano
Editor, Senior Moderator
Antiviral Res
. 2022 May 4;105329.
doi: 10.1016/j.antiviral.2022.105329. Online ahead of print.
Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection
Jared Pitts[SUP] 1 [/SUP], Darius Babusis[SUP] 1 [/SUP], Meghan S Vermillion[SUP] 2 [/SUP], Raju Subramanian[SUP] 1 [/SUP], Kim Barrett[SUP] 1 [/SUP], Diane Lye[SUP] 1 [/SUP], Bin Ma[SUP] 1 [/SUP], Xiaofeng Zhao[SUP] 1 [/SUP], Nicholas Riola[SUP] 1 [/SUP], Xuping Xie[SUP] 3 [/SUP], Adriana Kajon[SUP] 2 [/SUP], Xianghan Lu[SUP] 1 [/SUP], Roy Bannister[SUP] 1 [/SUP], Pei-Yong Shi[SUP] 3 [/SUP], Maria Toteva[SUP] 1 [/SUP], Danielle P Porter[SUP] 1 [/SUP], Bill J Smith[SUP] 1 [/SUP], Tomas Cihlar[SUP] 1 [/SUP], Richard Mackman[SUP] 1 [/SUP], John P Bilello[SUP] 4 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by the FDA for the treatment of COVID-19. The parent nucleoside of RDV, GS-441524, exhibits antiviral activity against numerous respiratory viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV in most assays. Here we find in both human alveolar and bronchial primary cells, GS-441524 is metabolized to the pharmacologically active GS-441524 triphosphate (TP) less efficiently than RDV, which correlates with a lower in vitro SARS-CoV-2 antiviral activity. In vivo, African green monkeys (AGM) orally dosed with GS-441524 yielded low plasma levels due to limited oral bioavailability of <10%. When GS-441524 was delivered via intravenous (IV) administration, although plasma concentrations of GS-441524 were significantly higher, lung TP levels were lower than observed from IV RDV. To determine the required systemic exposure of GS-441524 associated with in vivo antiviral efficacy, SARS-CoV-2 infected AGMs were treated with a once-daily IV dose of either 7.5 or 20 mg/kg GS-441524 or IV RDV for 5 days and compared to vehicle control. Despite the reduced lung TP formation compared to IV dosing of RDV, daily treatment with IV GS-441524 resulted in dose-dependent efficacy, with the 20 mg/kg GS-441524 treatment resulting in significant reductions of SARS-CoV-2 replication in the lower respiratory tract of infected animals. These findings demonstrate the in vivo SARS-CoV-2 antiviral efficacy of GS-441524 and support evaluation of its orally bioavailable prodrugs as potential therapies for COVID-19.
Keywords: African green monkey; GS-441524; Remdesivir; SARS-CoV-2.
. 2022 May 4;105329.
doi: 10.1016/j.antiviral.2022.105329. Online ahead of print.
Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection
Jared Pitts[SUP] 1 [/SUP], Darius Babusis[SUP] 1 [/SUP], Meghan S Vermillion[SUP] 2 [/SUP], Raju Subramanian[SUP] 1 [/SUP], Kim Barrett[SUP] 1 [/SUP], Diane Lye[SUP] 1 [/SUP], Bin Ma[SUP] 1 [/SUP], Xiaofeng Zhao[SUP] 1 [/SUP], Nicholas Riola[SUP] 1 [/SUP], Xuping Xie[SUP] 3 [/SUP], Adriana Kajon[SUP] 2 [/SUP], Xianghan Lu[SUP] 1 [/SUP], Roy Bannister[SUP] 1 [/SUP], Pei-Yong Shi[SUP] 3 [/SUP], Maria Toteva[SUP] 1 [/SUP], Danielle P Porter[SUP] 1 [/SUP], Bill J Smith[SUP] 1 [/SUP], Tomas Cihlar[SUP] 1 [/SUP], Richard Mackman[SUP] 1 [/SUP], John P Bilello[SUP] 4 [/SUP]
Affiliations
- PMID: 35525335
- DOI: 10.1016/j.antiviral.2022.105329
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by the FDA for the treatment of COVID-19. The parent nucleoside of RDV, GS-441524, exhibits antiviral activity against numerous respiratory viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV in most assays. Here we find in both human alveolar and bronchial primary cells, GS-441524 is metabolized to the pharmacologically active GS-441524 triphosphate (TP) less efficiently than RDV, which correlates with a lower in vitro SARS-CoV-2 antiviral activity. In vivo, African green monkeys (AGM) orally dosed with GS-441524 yielded low plasma levels due to limited oral bioavailability of <10%. When GS-441524 was delivered via intravenous (IV) administration, although plasma concentrations of GS-441524 were significantly higher, lung TP levels were lower than observed from IV RDV. To determine the required systemic exposure of GS-441524 associated with in vivo antiviral efficacy, SARS-CoV-2 infected AGMs were treated with a once-daily IV dose of either 7.5 or 20 mg/kg GS-441524 or IV RDV for 5 days and compared to vehicle control. Despite the reduced lung TP formation compared to IV dosing of RDV, daily treatment with IV GS-441524 resulted in dose-dependent efficacy, with the 20 mg/kg GS-441524 treatment resulting in significant reductions of SARS-CoV-2 replication in the lower respiratory tract of infected animals. These findings demonstrate the in vivo SARS-CoV-2 antiviral efficacy of GS-441524 and support evaluation of its orally bioavailable prodrugs as potential therapies for COVID-19.
Keywords: African green monkey; GS-441524; Remdesivir; SARS-CoV-2.