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Disruption of disulfides within RBD of SARS‐CoV‐2 spike protein prevents fusion and represents a target for viral entry inhibition by registered drugs
Author(s) -
MančekKeber Mateja,
HafnerBratkovič Iva,
Lainšček Duško,
Benčina Mojca,
Govednik Tea,
Orehek Sara,
Plaper Tjaša,
Jazbec Vid,
Bergant Valter,
Grass Vincent,
Pichlmair Andreas,
Jerala Roman
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100560r
Subject(s) - lipid bilayer fusion , viral entry , chemistry , spike (software development) , spike protein , microbiology and biotechnology , fusion protein , viral replication , ascorbic acid , cysteine , computational biology , covid-19 , biochemistry , virology , biology , virus , membrane , recombinant dna , medicine , gene , food science , management , disease , pathology , infectious disease (medical specialty) , economics , enzyme
The SARS‐CoV‐2 pandemic imposed a large burden on health and society. Therapeutics targeting different components and processes of the viral infection replication cycle are being investigated, particularly to repurpose already approved drugs. Spike protein is an important target for both vaccines and therapeutics. Insights into the mechanisms of spike‐ACE2 binding and cell fusion could support the identification of compounds with inhibitory effects. Here, we demonstrate that the integrity of disulfide bonds within the receptor‐binding domain (RBD) plays an important role in the membrane fusion process although their disruption does not prevent binding of spike protein to ACE2. Several reducing agents and thiol‐reactive compounds are able to inhibit viral entry. N‐acetyl cysteine amide, L‐ascorbic acid, JTT‐705, and auranofin prevented syncytia formation, viral entry into cells, and infection in a mouse model, supporting disulfides of the RBD as a therapeutically relevant target.