Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities

Xiu, Siyu; Dick, Alexej; Han, Jiuqiang; Mirzaie, Sako; Abdi, Fatemeh; Simon, Chantal; Zhan, Peng; Liu, Xinyong

doi:10.1021/acs.jmedchem.0c00502

Cited by 205 publications

(259 citation statements)

References 138 publications

(285 reference statements)

Supporting

Mentioning

244

Contrasting

Unclassified

Order By: Relevance

“…An intriguing way to tackle the SARS-CoV-2 infection is to disrupt the entrance of the virus into host cells by blocking the molecular machinery implied in this fundamental step [36,62,70,73]. The structural basis of the interaction between ACE2 and the S glycoprotein RBD (Figure 1) could drive the discovery of small molecules and monoclonal antibodies [8,52,66] able to slow down, or even prevent, the development of COVID-19 [7,27,39,74].…”

Section: Introductionmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

Preprint

View full text Add to dashboard Cite

The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting the importance of considering the dynamic formation of the heterodimer when judging any potential candidate.

show abstract

Section: Introductionmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In fact, this assay setup is very similar to one recently shown to work as a specific and sensitive SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of this same PPI (CoV-S-ACE2) (Tan et al, 2020). With this setup in our hands, we performed a preliminary screening of representative organic dyes from our in-house library plus a few compounds that are or have been considered of possible interest in inhibiting SAR-CoV-2 by different mechanisms of action, e.g., chloroquine, clemastine, and suramin (Colson et al, 2020;da Silva et al, 2020;Gordon et al, 2020;McKee et al, 2020;Xiu et al, 2020). Screening at 5 µM indicated that most have no activity and, hence, are unlikely to interfere with the S-protein -ACE2 binding needed for viral attachment.…”

Section: Resultsmentioning

confidence: 99%

Methylene Blue Inhibits In Vitro the SARS-CoV-2 Spike – ACE2 Protein-Protein Interaction – A Mechanism That Can Contribute to Its Antiviral Activity Against COVID-19

Bojadzic

Garnica

Buchwald

2020

Preprint

View full text Add to dashboard Cite

Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC50 = 3 μM) in our protein-based ELISA-type setup, while chloroquine, siramesine, and suramin showed no inhibitory activity in this assay. Erythrosine B, which we have shown before to be a promiscuous SMI of PPIs, also inhibited this interaction with an activity similar, possibly slightly higher, than those found for it for other PPIs. This PPI inhibitory activity of methylene blue could contribute to its antiviral activity against SARS-CoV-2 even in the absence of light by blocking its attachment to ACE2-expressing cells and making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.

show abstract

Section: Introductionmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

J Comput Aided Mol Des

View full text Add to dashboard Cite

The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.

show abstract

Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities

Cited by 205 publications

References 138 publications

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Methylene Blue Inhibits In Vitro the SARS-CoV-2 Spike – ACE2 Protein-Protein Interaction – A Mechanism That Can Contribute to Its Antiviral Activity Against COVID-19

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Contact Info

Product

Resources

About