RT Journal Article
SR Electronic
T1 Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.22.485299
DO 10.1101/2022.03.22.485299
A1 Chuang, Sung-Ting
A1 Papp, Henrietta
A1 Kuczmog, Anett
A1 Eells, Rebecca
A1 Condor Capcha, Jose M.
A1 Shehadeh, Lina A.
A1 Jakab, Ferenc
A1 Buchwald, Peter
YR 2022
UL http://biorxiv.org/content/early/2022/03/22/2022.03.22.485299.abstract
AB We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and used for other medical applications, as a small-molecule inhibitor of the protein-protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration-dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concerns such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1-5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63 – ACE2, hepatitis C virus E – CD81) as well as others (e.g., IL-2 – IL-2Rα) with similar potency. This non-specificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and it has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19.Competing Interest StatementThe authors have declared no competing interest.ACE2angiotensin converting enzyme 2CoVcoronavirusMeBlumethylene blueNBlBknaphthol blue blackPPIprotein-protein interactionSARSsevere acute respiratory syndromeSMIsmall-molecule inhibitorSPRsurface plasmon resonanceSYsunset yellow FCFTNFtumor necrosis factorVoCvariant of concern.