biostudies-literatureUnknownJana IDBLRD VANCI NIH HHSAs newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key towards sustenance. Here, we identify an evolutionary conserved E-L-L motif present within the HR2 domain of all human and non-human coronavirus spike (S) proteins that play a crucial role in stabilizing the post-fusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this E-L-L motif resulting in effective inhibition of SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy towards blocking S protein-mediated vibioRxiv : the preprint server for biology2022.03.16.484554https://www.ebi.ac.uk/biostudies/studies/S-EPMC8936095biostudies-literatureTargeting an evolutionarily conserved "E-L-L" motif in the spike protein to develop a small molecule fusion inhibitor against SARS-CoV-2.PMC8936095IK6 BX004212I01 BX005490IK6 BX003778R01 CA180758Banerjee SGhosh ADas AKBhattacharya PDas SMohapatra SSAditya SSrikrishnan SRoy AMcGill ARChandran BMohapatra SMondal AMayilsamy KBhattacharje GJana IDBasak ABhimsaria DfalseTargeting an evolutionarily conserved "E-L-L" motif in the spike protein to develop a small molecule fusion inhibitor against SARS-CoV-2.As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key towards sustenance. Here, we identify an evolutionary conserved E-L-L motif present within the HR2 domain of all human and non-human coronavirus spike (S) proteins that play a crucial role in stabilizing the post-fusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this E-L-L motif resulting in effective inhibition of SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy towards blocking S protein-mediated vi2022-01-01T00:00:00Z2022 Mar2026-04-08T17:31:46.134Z2024-11-21T02:17:34.112ZS-EPMC89360953531357510.1101/2022.03.16.484554