Dalcetrapib
Dalcetrapib (JTT-705) blocks SARS-CoV-2 cell fusion by disrupting spike protein disulfide bonds (FASEB J 2021)
Original title: Disruption of disulfides within RBD of SARS-CoV-2 spike protein prevents fusion and represents a target for viral entry inhibition by registered drugs
This study investigated whether disulfide bonds within the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are required for membrane fusion, finding that disrupting these bonds prevented fusion even though it did not block spike protein binding to ACE2. Testing thiol-reactive compounds for this activity, the authors identified N-acetyl cysteine amide, L-ascorbic acid, dalcetrapib (under its research name JTT-705), and auranofin as agents that prevented syncytia formation and viral entry into cells and blocked infection in a mouse model, supporting the disulfide bonds of the spike RBD as a therapeutically relevant target and identifying dalcetrapib as one of the drugs capable of exploiting it for viral entry inhibition.
Original abstract
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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.