tetano
Editor, Senior Moderator
Nat Commun
. 2021 Jun 3;12(1):3309.
doi: 10.1038/s41467-021-23328-0.
Drug repurposing screens identify chemical entities for the development of COVID-19 interventions
Malina A Bakowski[SUP] #[/SUP][SUP] 1 [/SUP], Nathan Beutler[SUP] #[/SUP][SUP] 2 [/SUP], Karen C Wolff[SUP] 3 [/SUP], Melanie G Kirkpatrick[SUP] 3 [/SUP], Emily Chen[SUP] 3 [/SUP], Tu-Trinh H Nguyen[SUP] 3 [/SUP], Laura Riva[SUP] 3 [/SUP], Namir Shaabani[SUP] 2 [/SUP], Mara Parren[SUP] 2 [/SUP], James Ricketts[SUP] 2 [/SUP], Anil K Gupta[SUP] 3 [/SUP], Kastin Pan[SUP] 3 [/SUP], Peiting Kuo[SUP] 3 [/SUP], MacKenzie Fuller[SUP] 4 5 [/SUP], Elijah Garcia[SUP] 2 [/SUP], John R Teijaro[SUP] 2 [/SUP], Linlin Yang[SUP] 2 [/SUP], Debashis Sahoo[SUP] 6 7 [/SUP], Victor Chi[SUP] 3 [/SUP], Edward Huang[SUP] 3 [/SUP], Natalia Vargas[SUP] 3 [/SUP], Amanda J Roberts[SUP] 8 [/SUP], Soumita Das[SUP] 5 9 [/SUP], Pradipta Ghosh[SUP] 4 5 10 [/SUP], Ashley K Woods[SUP] 3 [/SUP], Sean B Joseph[SUP] 3 [/SUP], Mitchell V Hull[SUP] 3 [/SUP], Peter G Schultz[SUP] 3 [/SUP], Dennis R Burton[SUP] 2 [/SUP], Arnab K Chatterjee[SUP] 3 [/SUP], Case W McNamara[SUP] 3 [/SUP], Thomas F Rogers[SUP] 11 12 [/SUP]
Affiliations
Abstract
The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.
. 2021 Jun 3;12(1):3309.
doi: 10.1038/s41467-021-23328-0.
Drug repurposing screens identify chemical entities for the development of COVID-19 interventions
Malina A Bakowski[SUP] #[/SUP][SUP] 1 [/SUP], Nathan Beutler[SUP] #[/SUP][SUP] 2 [/SUP], Karen C Wolff[SUP] 3 [/SUP], Melanie G Kirkpatrick[SUP] 3 [/SUP], Emily Chen[SUP] 3 [/SUP], Tu-Trinh H Nguyen[SUP] 3 [/SUP], Laura Riva[SUP] 3 [/SUP], Namir Shaabani[SUP] 2 [/SUP], Mara Parren[SUP] 2 [/SUP], James Ricketts[SUP] 2 [/SUP], Anil K Gupta[SUP] 3 [/SUP], Kastin Pan[SUP] 3 [/SUP], Peiting Kuo[SUP] 3 [/SUP], MacKenzie Fuller[SUP] 4 5 [/SUP], Elijah Garcia[SUP] 2 [/SUP], John R Teijaro[SUP] 2 [/SUP], Linlin Yang[SUP] 2 [/SUP], Debashis Sahoo[SUP] 6 7 [/SUP], Victor Chi[SUP] 3 [/SUP], Edward Huang[SUP] 3 [/SUP], Natalia Vargas[SUP] 3 [/SUP], Amanda J Roberts[SUP] 8 [/SUP], Soumita Das[SUP] 5 9 [/SUP], Pradipta Ghosh[SUP] 4 5 10 [/SUP], Ashley K Woods[SUP] 3 [/SUP], Sean B Joseph[SUP] 3 [/SUP], Mitchell V Hull[SUP] 3 [/SUP], Peter G Schultz[SUP] 3 [/SUP], Dennis R Burton[SUP] 2 [/SUP], Arnab K Chatterjee[SUP] 3 [/SUP], Case W McNamara[SUP] 3 [/SUP], Thomas F Rogers[SUP] 11 12 [/SUP]
Affiliations
- PMID: 34083527
- DOI: 10.1038/s41467-021-23328-0
Abstract
The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.