Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein

Wang, Lin; Wu, Yan; Yao, Sheng; Ge, Huan; Zhu, Yun; Chen, Kun; Chen, Wenzhang; Zhang, Yi; Zhu, Wei; Wang, Hongyang; Guo, Yu; Ma, Peixiang; Ren, Pengxuan; Zhang, Xiang-Lei; Li, Hui-Qiong; Ali, Mohammad Ajmal; Xu, Wenqing; Jiang, Hualiang; Zhang, Leike; Zhu, Lili; Yang, Ye; Shang, Weijuan; Bai, Fang

doi:10.1038/s41401-021-00735-z

Cited by 44 publications

(37 citation statements)

References 55 publications

(25 reference statements)

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“…Bio-layer interferometry allows the calculation of the association rate (k on ), dissociation rate (k dis ) and dissociation constant (K D ). This technique has been adopted to screen RBD ligands [17,48] in combination with virtual screening [49,50]. The results of the bio-layer experiments are presented in Table 1.…”

Section: Bio-layer Interferometrymentioning

confidence: 99%

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

Coghi

Yang

et al. 2021

Pharmaceuticals

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Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 μM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 μM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the μM range, supporting the in silico data.

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Section: Bio-layer Interferometrymentioning

confidence: 99%

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

Coghi

Yang

et al. 2021

Pharmaceuticals

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“…Furthermore, antibodies are very large molecules, which may hamper tissue penetration, as well as access to sterically shielded epitopes. Therefore, current research is also focused on developing alternative, smaller molecules capable of interfering with the interaction of the SARS-CoV-2 spike protein with cellular ACE2 [ 12 , 13 , 14 , 15 ]. Over the past two years, a range of studies have reported the computational design of smaller proteins or peptides, either based on the structure of the two N-terminal α-helices of ACE2, through which it contacts the receptor binding domain (RBD) of the SARS-CoV-2 spike protein [ 16 , 17 , 18 , 19 ], or through de novo design based on the RBD structure [ 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

Weißenborn

Richel

Hüseman

et al. 2022

IJMS

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Based on the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, we have generated and characterized truncated peptide variants of LCB1, which present only two of the three LCB1 helices, and which fully retained the virus neutralizing potency against different SARS-CoV-2 variants of concern (VOC). This antiviral activity was even 10-fold stronger for a cyclic variant of the two-helix peptides, as compared to the full-length peptide. Furthermore, the proteolytic stability of the cyclic peptide was substantially improved, rendering it a better potential candidate for SARS-CoV-2 therapy. In a more mechanistic approach, the peptides also served as tools to dissect the role of individual mutations in the RBD for the susceptibility of the resulting virus variants to neutralization by the peptides. As the peptides reported here were generated through chemical synthesis, rather than recombinant protein expression, they are amenable to further chemical modification, including the incorporation of a wide range of non-proteinogenic amino acids, with the aim to further stabilize the peptides against proteolytic degradation, as well as to improve the strength, as well the breadth, of their virus neutralizing capacity.

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“…Importantly, the binding of Cipa ligands at the RBD engages the same set of amino acid residues which are responsible for the SARS-CoV2 spike interaction with receptor ACE2 (PDB ID: 6M0J). Moreover, Salutaridine binding at the RBD is found to be structurally reminiscent with comparable free energy of binding of H69D1(∆G binding -6.8 kcal/mol), a potent spike protein targeting SARS-CoV2 entry blocker (used as the positive control) [ 26 ]. The free energy of binding of all tested Cipa bioactive compounds at the RBD-ACE2 interface stabilizing residues are also found to be energetically favourable compared to the free energy of dissociation of RBD-ACE2 complex [∆G diss -2.00 kcal/mol; calculated by PDBePISA [ 27 ]].…”

Section: Resultsmentioning

confidence: 99%

Anti-SARS-CoV-2 potential of Cissampelos pareira L. identified by connectivity map-based analysis and in vitro studies

Haider

Anand

Enayathullah

et al. 2022

BMC Complement Med Ther

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Background Viral infections have a history of abrupt and severe eruptions through the years in the form of pandemics. And yet, definitive therapies or preventive measures are not present. Herbal medicines have been a source of various antiviral compounds such as Oseltamivir, extracted using shikimic acid from star anise (Illicium verum) and Acyclovir from Carissa edulis are FDA (Food and Drug Administration) approved antiviral drugs. In this study, we dissect the anti-coronavirus infection activity of Cissampelos pareira L (Cipa) extract using an integrative approach. Methods We analysed the signature similarities between predicted antiviral agents and Cipa using the connectivity map (https://clue.io/). Next, we tested the anti-SARS-COV-2 activity of Cipa in vitro. Molecular docking analyses of constituents of with key targets of SARS-CoV2 protein viz. spike protein, RNA‑dependent RNA‑polymerase (RdRp) and 3C‑like proteinase. was also performed. A three-way comparative analysis of Cipa transcriptome, COVID-19 BALF transcriptome and CMAP signatures of small compounds was also performed. Results Several predicted antivirals showed a high positive connectivity score with Cipa such as apcidin, emetine, homoharringtonine etc. We also observed 98% inhibition of SARS-COV-2 replication in infected Vero cell cultures with the whole extract. Some of its prominent pure constituents e.g. pareirarine, cissamine, magnoflorine exhibited 40–80% inhibition. Comparison of genes between BALF and Cipa showed an enrichment of biological processes like transcription regulation and response to lipids, to be downregulated in Cipa while being upregulated in COVID-19. CMAP also showed that Triciribine, torin-1 and VU-0365114–2 had positive connectivity with BALF 1 and 2, and negative connectivity with Cipa. Amongst all the tested compounds, Magnoflorine and Salutaridine exhibited the most potent and consistent strong in silico binding profiles with SARS-CoV2 therapeutic targets.

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Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein

Cited by 44 publications

References 55 publications

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2)

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

Anti-SARS-CoV-2 potential of Cissampelos pareira L. identified by connectivity map-based analysis and in vitro studies

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