tetano
Editor, Senior Moderator
J Virol
. 2021 Sep 22;JVI0143721.
doi: 10.1128/JVI.01437-21. Online ahead of print.
Discovery and evaluation of entry inhibitors for SARS-CoV-2 and its emerging variants
Arpan Acharya[SUP] 1 [/SUP], Kabita Pandey[SUP] 1 [/SUP], Michellie Thurman[SUP] 1 [/SUP], Elizabeth Klug[SUP] 1 [/SUP], Jay Trivedi[SUP] 1 [/SUP], Kalicharan Sharma[SUP] 2 [/SUP], Christian L Lorson[SUP] 3 4 [/SUP], Kamal Singh[SUP] 3 4 5 [/SUP], Siddappa N Byrareddy[SUP] 1 5 6 7 [/SUP]
Affiliations
Abstract
The outbreak of SARS-CoV-2 is responsible for the COVID-19 pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design (CADD) approach, we identified and validated 5 potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both the compounds showed antiviral activity with IC[SUB]50[/SUB] values in the micromolar range (MU-UNMC-1: IC[SUB]50[/SUB]= 0.67 μM and MU-UNMC-2: IC[SUB]50[/SUB]= 1.72 μM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC[SUB]50[/SUB]= 9.27 μM & 3.00 μM) and Scotland variant B.1.222 (IC[SUB]50[/SUB]= 2.64 μM & 1.39 μM) respectively. Following these assays, we conducted 'induced-fit (flexible) docking' to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir (RDV), the only approved drug for treating hospitalized COVID-19 patients. IMPORTANCE The ongoing coronavirus infectious disease 2019 (COVID-19) pandemic is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More than 207 million people have been infected globally, and 4.3 million have died due to this viral outbreak. While a few vaccines have been deployed, a SARS-CoV-2 specific antiviral for the treatment of COVID-19 is yet to be approved. As the interaction of SARS-CoV-2 spike protein with ACE2 is critical for cellular entry, using a combination of a computer-aided drug design (CADD) approach and cell-based in vitro assays, we report the identification of five potential SARS-CoV-2 entry inhibitors. Out of the five, two compounds (MU-UNMC-1 and MU-UNMC-2) have antiviral activity against ancestral SARS-CoV-2 and emerging variants from South Africa and Scotland. Furthermore, MU-UNMC-2 acts synergistically with remdesivir, suggesting that RDV and MU-UNMC-2 can be developed as a combination therapy to treat COVID-19, infected individuals.
. 2021 Sep 22;JVI0143721.
doi: 10.1128/JVI.01437-21. Online ahead of print.
Discovery and evaluation of entry inhibitors for SARS-CoV-2 and its emerging variants
Arpan Acharya[SUP] 1 [/SUP], Kabita Pandey[SUP] 1 [/SUP], Michellie Thurman[SUP] 1 [/SUP], Elizabeth Klug[SUP] 1 [/SUP], Jay Trivedi[SUP] 1 [/SUP], Kalicharan Sharma[SUP] 2 [/SUP], Christian L Lorson[SUP] 3 4 [/SUP], Kamal Singh[SUP] 3 4 5 [/SUP], Siddappa N Byrareddy[SUP] 1 5 6 7 [/SUP]
Affiliations
- PMID: 34550770
- DOI: 10.1128/JVI.01437-21
Abstract
The outbreak of SARS-CoV-2 is responsible for the COVID-19 pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design (CADD) approach, we identified and validated 5 potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both the compounds showed antiviral activity with IC[SUB]50[/SUB] values in the micromolar range (MU-UNMC-1: IC[SUB]50[/SUB]= 0.67 μM and MU-UNMC-2: IC[SUB]50[/SUB]= 1.72 μM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC[SUB]50[/SUB]= 9.27 μM & 3.00 μM) and Scotland variant B.1.222 (IC[SUB]50[/SUB]= 2.64 μM & 1.39 μM) respectively. Following these assays, we conducted 'induced-fit (flexible) docking' to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir (RDV), the only approved drug for treating hospitalized COVID-19 patients. IMPORTANCE The ongoing coronavirus infectious disease 2019 (COVID-19) pandemic is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More than 207 million people have been infected globally, and 4.3 million have died due to this viral outbreak. While a few vaccines have been deployed, a SARS-CoV-2 specific antiviral for the treatment of COVID-19 is yet to be approved. As the interaction of SARS-CoV-2 spike protein with ACE2 is critical for cellular entry, using a combination of a computer-aided drug design (CADD) approach and cell-based in vitro assays, we report the identification of five potential SARS-CoV-2 entry inhibitors. Out of the five, two compounds (MU-UNMC-1 and MU-UNMC-2) have antiviral activity against ancestral SARS-CoV-2 and emerging variants from South Africa and Scotland. Furthermore, MU-UNMC-2 acts synergistically with remdesivir, suggesting that RDV and MU-UNMC-2 can be developed as a combination therapy to treat COVID-19, infected individuals.