CD40-targeting KGYY15 peptides do not efficiently block the CD40–CD40L interaction

Bojadzic, Damir; Buchwald, Péter

doi:10.1007/s00125-019-04996-6

Cited by 5 publications

(10 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Having access to broadly cross-reactive agents that can neutralize a wide range of antigenically disparate viruses that share similar pathogenic outcomes would be highly valuable from a therapeutic perspective (17), and SMIs are less specific and could yield therapies that are more broadly active (i.e., less strain-and mutation-sensitive) than antibodies, which tend to be highly specific. We have shown before that while the corresponding antibodies are species specific for the CD40-CD40L PPI, our SMIs could inhibit both the human and mouse system with similar potencies (53,54). Hence, it is feasible that SMI structures can be identified that in addition to inhibiting SARS-CoV-2, also inhibit other CoVs, including the high lethality SARS-CoV and MERS-CoV as well as the common cold causing HCoVs.…”

Section: Discussionmentioning

confidence: 85%

“…For example, we have shown that while the corresponding antibodies did not cross-react for the human vs mouse CD40-CD40L PPI, our SMIs did so and had about similar potencies (53,54).…”

Section: Introductionmentioning

confidence: 84%

“…Since previously we found that starting from organic dyes one can identify SMIs for cosignaling PPIs as potential immunomodulatory agents (48,(53)(54)(55)(56)(57)(58)(59), we initiated a screen of such compounds for their ability to inhibit the SARS-CoV-2-S-ACE2 PPI. This led to the identification of several organic dyes (1-5, Figure 1) that show promising inhibitory activity of this PPI in vitro, including methylene blue (6), a phenothiazine dye approved by the FDA for the treatment of methemoglobinemia, which we have described separately (60).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Small-MoleculeIn VitroInhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Bojadzic

Garnica

Chen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Inhibitors of the protein-protein interaction (PPI) between the SARS-CoV-2 spike protein and ACE2, which acts as a ligand-receptor pair that initiates the viral attachment and cellular entry of this coronavirus causing the ongoing COVID-19 pandemic, are of considerable interest as potential antiviral agents. While blockade of such PPIs with small molecules is more challenging than with antibodies, small-molecule inhibitors (SMIs) might offer alternatives that are less strain- and mutation-sensitive, suitable for oral or inhaled administration, and more controllable / less immunogenic. Here, we report the identification of SMIs of this PPI by screening our compound-library that is focused on the chemical space of organic dyes. Among promising candidates identified, several dyes (Congo red, direct violet 1, Evans blue) and novel drug-like compounds (DRI-C23041, DRI-C91005) inhibited the interaction of hACE2 with the spike proteins of SARS-CoV-2 as well as SARS-CoV with low micromolar activity in our cell-free ELISA-type assays (IC50s of 0.2-3.0 μM); whereas, control compounds, such as sunset yellow FCF, chloroquine, and suramin, showed no activity. Protein thermal shift assays indicated that the SMIs identified here bind SARS-CoV-2-S and not ACE2. Selected promising compounds inhibited the entry of a SARS-CoV-2-S expressing pseudovirus into ACE2-expressing cells in concentration-dependent manner with low micromolar IC50s (6-30 μM). This provides proof-of-principle evidence for the feasibility of small-molecule inhibition of PPIs critical for coronavirus attachment/entry and serves as a first guide in the search for SMI-based alternative antiviral therapies for the prevention and treatment of diseases caused by coronaviruses in general and COVID-19 in particular.

show abstract

Section: Discussionmentioning

confidence: 85%

“…For example, we have shown that while the corresponding antibodies did not cross-react for the human vs mouse CD40-CD40L PPI, our SMIs did so and had about similar potencies (53,54).…”

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Small-MoleculeIn VitroInhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Bojadzic

Garnica

Chen

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have shown before that while the corresponding antibodies are species specific for the CD40–CD40L PPI, our SMIs could inhibit both the human and mouse system with similar potencies. 56 , 57 Hence, it is feasible that SMI structures can be identified that in addition to inhibiting SARS-CoV-2, also inhibit other CoVs, including the high lethality SARS-CoV and MERS-CoV as well as the common cold causing HCoVs. Along these lines, it is very encouraging that SMIs identified here target the CoV-S protein and not ACE2 ( Figure 6 ) and they show similar potency in inhibiting SARS-CoV ( Figure 4 ) and SARS-CoV-2 ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…For example, we have shown that while the corresponding antibodies did not cross-react for the human vs mouse CD40–CD40L PPI, our SMIs did so and had about similar potencies. 56 , 57 …”

mentioning

confidence: 99%

Small-Molecule Inhibitors of the Coronavirus Spike: ACE2 Protein–Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

et al. 2021

Self Cite

View full text Add to dashboard Cite

Inhibitors of the protein–protein interaction (PPI) between the SARS-CoV-2 spike protein and human ACE2 (hACE2), which acts as a ligand–receptor pair that initiates the viral attachment and cellular entry of this coronavirus causing the ongoing COVID-19 pandemic, are of considerable interest as potential antiviral agents. While blockade of such PPIs with small molecules is more challenging than that with antibodies, small-molecule inhibitors (SMIs) might offer alternatives that are less strain- and mutation-sensitive, suitable for oral or inhaled administration, and more controllable/less immunogenic. Here, we report the identification of SMIs of this PPI by screening our compound library focused around the chemical space of organic dyes. Among promising candidates identified, several dyes (Congo red, direct violet 1, Evans blue) and novel druglike compounds (DRI-C23041, DRI-C91005) inhibited the interaction of hACE2 with the spike proteins of SARS-CoV-2 as well as SARS-CoV with low micromolar activity in our cell-free ELISA-type assays (IC 50 ’s of 0.2–3.0 μM), whereas control compounds, such as sunset yellow FCF, chloroquine, and suramin, showed no activity. Protein thermal shift assays indicated that the SMIs of interest identified here bind SARS-CoV-2-S and not hACE2. While dyes seemed to be promiscuous inhibitors, DRI-C23041 showed some selectivity and inhibited the entry of two different SARS-CoV-2-S expressing pseudoviruses into hACE2-expressing cells in a concentration-dependent manner with low micromolar IC 50 ’s (6–7 μM). This provides proof-of-principle evidence for the feasibility of small-molecule inhibition of PPIs critical for SARS-CoV-2 attachment/entry and serves as a first guide in the search for SMI-based alternative antiviral therapies for the prevention and treatment of diseases caused by coronaviruses in general and COVID-19 in particular.

show abstract

Modulating CD40 and integrin signaling in the proinflammatory nexus using a 15-amino-acid peptide, KGYY15

Vaitaitis¹,

Wagner²

2023

Journal of Biological Chemistry

View full text Add to dashboard Cite

CD40-targeting KGYY15 peptides do not efficiently block the CD40–CD40L interaction

Cited by 5 publications

References 7 publications

Small-MoleculeIn VitroInhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Small-MoleculeIn VitroInhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Small-Molecule Inhibitors of the Coronavirus Spike: ACE2 Protein–Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Modulating CD40 and integrin signaling in the proinflammatory nexus using a 15-amino-acid peptide, KGYY15

Contact Info

Product

Resources

About