Targeting an evolutionarily conserved "E-L-L" motif in the spike protein to develop a small molecule fusion inhibitor against SARS-CoV-2.

Autor:	Jana ID; School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, India., Bhattacharya P; Department of Chemistry, Mrinalini Datta Mahavidyapith, Kolkata, India., Mayilsamy K; Department of Molecular Medicine, University of South Florida, Tampa, USA.; Department of Veterans Affairs, James A Haley Veterans Hospital, Tampa, USA., Banerjee S; School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, India., Bhattacharje G; Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India., Das S; School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, India., Aditya S; School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, India., Ghosh A; Department of Molecular Medicine, University of South Florida, Tampa, USA., McGill AR; Department of Molecular Medicine, University of South Florida, Tampa, USA.; Department of Internal Medicine, University of South Florida, Tampa, USA.; Department of Veterans Affairs, James A Haley Veterans Hospital, Tampa, USA., Srikrishnan S; Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India., Das AK; Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India., Basak A; Division of Chemical Science, Indian Institute of Science Education and Research Kolkata, Mohanpur, India., Mohapatra SS; Department of Internal Medicine, University of South Florida, Tampa, USA.; Department of Veterans Affairs, James A Haley Veterans Hospital, Tampa, USA., Chandran B; Department of Molecular Medicine, University of South Florida, Tampa, USA., Bhimsaria D; Bioinformaticals, Jaipur, India., Mohapatra S; Department of Molecular Medicine, University of South Florida, Tampa, USA.; Department of Veterans Affairs, James A Haley Veterans Hospital, Tampa, USA., Roy A; Department of Molecular Medicine, University of South Florida, Tampa, USA., Mondal A; School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, India.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2022 Mar 21. Date of Electronic Publication: 2022 Mar 21.
DOI:	10.1101/2022.03.16.484554
Abstrakt:	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 viral entry, mutations within the E-L-L 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 E-L-L motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.
Databáze:	MEDLINE
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