tetano
Editor, Senior Moderator
SLAS Discov
. 2021 Oct 23;S2472-5552(21)00012-5.
doi: 10.1016/j.slasd.2021.10.012. Online ahead of print.
Identification of potent small molecule inhibitors of SARS-CoV-2 entry
Sonia Mediouni[SUP] 1 [/SUP], Huihui Mou[SUP] 1 [/SUP], Yuka Otsuka[SUP] 2 [/SUP], Joseph Anthony Jablonski[SUP] 1 [/SUP], Robert Scott Adcock[SUP] 3 [/SUP], Lalit Batra[SUP] 3 [/SUP], Dong-Hoon Chung[SUP] 3 [/SUP], Christopher Rood[SUP] 4 [/SUP], Ian Mitchelle S de Vera[SUP] 4 [/SUP], Ronald Rahaim Jr[SUP] 2 [/SUP], Sultan Ullah[SUP] 2 [/SUP], Xuerong Yu[SUP] 2 [/SUP], Yulia A Getmanenko[SUP] 2 [/SUP], Nicole M Kennedy[SUP] 2 [/SUP], Chao Wang[SUP] 2 [/SUP], Tu-Trinh Nguyen[SUP] 5 [/SUP], Mitchell Hull[SUP] 5 [/SUP], Emily Chen[SUP] 5 [/SUP], Thomas D Bannister[SUP] 2 [/SUP], Pierre Baillargeon[SUP] 2 [/SUP], Louis Scampavia[SUP] 2 [/SUP], Michael Farzan[SUP] 1 [/SUP], Susana T Valente[SUP] 1 [/SUP], Timothy P Spicer[SUP] 6 [/SUP]
Affiliations
Abstract
The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants.
Keywords: Anti-viral drugs; HTS; Inhibitor; SARS-CoV-2; Virus entry.
. 2021 Oct 23;S2472-5552(21)00012-5.
doi: 10.1016/j.slasd.2021.10.012. Online ahead of print.
Identification of potent small molecule inhibitors of SARS-CoV-2 entry
Sonia Mediouni[SUP] 1 [/SUP], Huihui Mou[SUP] 1 [/SUP], Yuka Otsuka[SUP] 2 [/SUP], Joseph Anthony Jablonski[SUP] 1 [/SUP], Robert Scott Adcock[SUP] 3 [/SUP], Lalit Batra[SUP] 3 [/SUP], Dong-Hoon Chung[SUP] 3 [/SUP], Christopher Rood[SUP] 4 [/SUP], Ian Mitchelle S de Vera[SUP] 4 [/SUP], Ronald Rahaim Jr[SUP] 2 [/SUP], Sultan Ullah[SUP] 2 [/SUP], Xuerong Yu[SUP] 2 [/SUP], Yulia A Getmanenko[SUP] 2 [/SUP], Nicole M Kennedy[SUP] 2 [/SUP], Chao Wang[SUP] 2 [/SUP], Tu-Trinh Nguyen[SUP] 5 [/SUP], Mitchell Hull[SUP] 5 [/SUP], Emily Chen[SUP] 5 [/SUP], Thomas D Bannister[SUP] 2 [/SUP], Pierre Baillargeon[SUP] 2 [/SUP], Louis Scampavia[SUP] 2 [/SUP], Michael Farzan[SUP] 1 [/SUP], Susana T Valente[SUP] 1 [/SUP], Timothy P Spicer[SUP] 6 [/SUP]
Affiliations
- PMID: 35058179
- DOI: 10.1016/j.slasd.2021.10.012
Abstract
The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants.
Keywords: Anti-viral drugs; HTS; Inhibitor; SARS-CoV-2; Virus entry.