{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T18:13:49Z","timestamp":1768500829311,"version":"3.49.0"},"posted":{"date-parts":[[2022,3,16]]},"group-title":"Biochemistry","reference-count":65,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,3,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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 \u201cE-L-L\u201d 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 \u201cE-L-L\u201d motif resulting in effective inhibition of SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy towards blocking S protein-mediated viral entry, mutations within the \u201cE-L-L\u201d motif rendered the protein completely resistant to the drug, establishing its specificity towards this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective towards all major variants of concerns of SARS-CoV-2 including beta, kappa, delta, and omicron. Together, we show that this conserved essential \u201cE-L-L\u201d motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.<\/jats:p>","DOI":"10.1101\/2022.03.16.484554","type":"posted-content","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T22:27:54Z","timestamp":1647469674000},"source":"Crossref","is-referenced-by-count":1,"title":["Targeting an evolutionarily conserved \u201cE-L-L\u201d motif in the spike protein to develop a small molecule fusion inhibitor against SARS-CoV-2"],"prefix":"10.64898","author":[{"given":"Indrani","family":"Das Jana","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prabuddha","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karthick","family":"Mayilsamy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saptarshi","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gourab","family":"Bhattacharje","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayan","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seemanti","family":"Aditya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anandita","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew R.","family":"McGill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syamanthak","family":"Srikrishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit Kumar","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Basak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyam S.","family":"Mohapatra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bala","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devesh","family":"Bhimsaria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subhra","family":"Mohapatra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arunava","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arindam","family":"Mondal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"1","key":"2022032210500544000_2022.03.16.484554v2.1","first-page":"1","article-title":"Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase","volume":"11","year":"2021","journal-title":"Scientific Reports"},{"key":"2022032210500544000_2022.03.16.484554v2.2","first-page":"19","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","year":"2015","journal-title":"SoftwareX"},{"key":"2022032210500544000_2022.03.16.484554v2.3","doi-asserted-by":"crossref","unstructured":"Atul Patel , Ketan Patel , Kamlesh Patel , Kinjal Shah , & Arunaloke Chakrabarti . 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