Small-Molecule<i>In Vitro</i>Inhibitors of the Coronavirus Spike – ACE2 Protein-Protein Interaction as Blockers of Viral Attachment and Entry for SARS-CoV-2

Bojadzic, Damir; Garnica, Óscar; Chen, Jinshui; Buchwald, Péter

doi:10.1101/2020.10.22.351056

Cited by 5 publications

(4 citation statements)

References 111 publications

(159 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the time of the dreadful pandemic, cyclic and macrocyclic peptides could also play an important role in the search for antiviral agents. It is now fairly well established that the virus spike protein interacts with ACE2 and neuropilin-1 receptors through protein–protein interactions [ 103 , 104 , 105 ]. Similarly, the main protease (Mpro) of SARS-CoV-2, the causative etiological agent of COVID-19, is a transient homodimer indispensable for processing virus essential proteins [ 106 ].…”

Section: Discussionmentioning

confidence: 99%

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

2021

View full text Add to dashboard Cite

Cyclic and macrocyclic peptides constitute advanced molecules for modulating protein–protein interactions (PPIs). Although still peptide derivatives, they are metabolically more stable than linear counterparts, and should have a lower degree of flexibility, with more defined secondary structure conformations that can be adapted to imitate protein interfaces. In this review, we analyze recent progress on the main methods to access cyclic/macrocyclic peptide derivatives, with emphasis in a few selected examples designed to interfere within PPIs. These types of peptides can be from natural origin, or prepared by biochemical or synthetic methodologies, and their design could be aided by computational approaches. Some advances to facilitate the permeability of these quite big molecules by conjugation with cell penetrating peptides, and the incorporation of β-amino acid and peptoid structures to improve metabolic stability, are also commented. It is predicted that this field of research could have an important future mission, running in parallel to the discovery of new, relevant PPIs involved in pathological processes.

show abstract

Section: Discussionmentioning

confidence: 99%

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

2021

View full text Add to dashboard Cite

show abstract

“…All the ten ligands had negative results as modulators of cyclooxygenase-2, beta (2 and 3) adrenergic receptors, vascular endothelial growth factor receptors (1 and 2), dopamine D1 receptor, calcitonin gene-related peptide type 1 receptor, receptor protein-tyrosine kinase erbB-2, adenosine A2a receptor, dopamine D2 receptor, glutamate NMDA receptor, androgen receptor, dopamine transporter, serotonin 3a (5-HT3a) receptor, histamine H1 receptor, melatonin receptor 1B, adenosine A2b receptor, beta-1 adrenergic receptor, serotonin 4 (5-HT4) receptor, alpha-1a adrenergic receptor, sigma opioid receptor, adenosine A3 receptor, peroxisome proliferator-activated receptor gamma, delta-opioid receptor, sodium channel protein type IX alpha subunit, norepinephrine transporter, P2X purinoceptor (3 and 7), adenosine A1 receptor, endothelin receptor ET-B, vascular endothelial growth factor receptor and serotonin 7 (5-HT7) receptor, endothelin receptor ET-A. References [57][58][59][60][61][62][63] are cited in the supplementary materials.…”

Section: Supplementary Materialsmentioning

confidence: 99%

Effect of the N501Y Mutation on Ligands Complexed with SARS-CoV-2 RBD: Insights on Potential Drug Candidates for COVID-19

da Silva,

Camalhonte,

de Oliveira Almeida

et al. 2023

DDC

View full text Add to dashboard Cite

Bioactive compounds against SARS-CoV-2 targets could be potential treatments for COVID-19. Inhibitors of the receptor-binding domain (RBD) on the viral spike protein can block its binding to the human angiotensin-converting enzyme type II (ACE2) receptor. This study presents ligands based on natural products and synthetic compounds, targeting multiple N501/Y501 RBDs, besides RBD-ACE2, over different regions. The selected compounds were evaluated by docking using consensus scoring, pharmacokinetics/toxicological analyses, and molecular dynamics. Additionally, N501/Y501 RBD-ACE2 interaction properties and RBD–ligand complexes were compared. We identified that coenzyme Q10, 1-stearoyl-2-arachidonoylglycerol, and palmitone showed the greatest RBD interactions. Targeting specific residues (in particular, tyrosine) in the C-, N-terminal, and central RBD sites promoted more stable protein–ligand interactions than in the N-terminal region only. Our results indicate that the molecules had more energetically favorable interactions with residues from distinct RBD regions rather than only interacting with residues in the N-terminal site. Moreover, the compounds might better interact with mutated N501Y than N501 RBDs. These hits can be optimized to leads and investigated through QSAR models and biological assays to comprehend mechanisms better. Altogether, such strategies may anticipate antiviral strategies if or when future variants and other CoVs arise.

show abstract

“…Pharmaceutical companies such as Moderna and AstraZeneca have invented vaccines that are based on the genetic sequence of spike protein[ 11 , 12 ]. There are reports of small molecule inhibitors, monoclonal antibodies, and peptides that block the interaction of RBD with ACE2[ 10 , [13] , [14] , [15] ]. Above mentioned therapeutic strategies might have high effectiveness against SARS-CoV-2 but they are costly and time-consuming.…”

Section: Introductionmentioning

confidence: 99%

Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations

Kumar

Liu

2021

Computers in Biology and Medicine

View full text Add to dashboard Cite

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused worldwide pandemic and is responsible for millions of worldwide deaths due to -a respiratory disease known as COVID-19. In the search for a cure of COVID-19, drug repurposing is a fast and cost-effective approach to identify anti-COVID-19 drugs from existing drugs. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein has been a main target for drug designs to block spike protein binding to ACE2 proteins. In this study, we probed the conformational plasticity of the RBD using long molecular dynamics (MD) simulations, from which, representative conformations were identified using clustering analysis. Three simulated conformations and the original crystal structure were used to screen FDA approved drugs (2466 drugs) against the predicted binding site at the ACE2-RBD interface, leading to 18 drugs with top docking scores. Notably, 16 out of the 18 drugs were obtained from the simulated conformations, while the crystal structure suggests poor binding. The binding stability of the 18 drugs were further investigated using MD simulations. Encouragingly, 6 drugs exhibited stable binding with RBD at the ACE2-RBD interface and 3 of them (gonadorelin, fondaparinux and atorvastatin) showed significantly enhanced binding after the MD simulations. Our study shows that flexibility modeling of SARS-CoV-2 RBD using MD simulation is of great help in identifying novel agents which might block the interaction between human ACE2 and the SARS-CoV-2 RBD for inhibiting the virus infection.

show abstract

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

Cited by 5 publications

References 111 publications

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

Effect of the N501Y Mutation on Ligands Complexed with SARS-CoV-2 RBD: Insights on Potential Drug Candidates for COVID-19

Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations

Contact Info

Product

Resources

About