Molecular characterization of COVID-19 therapeutics: luteolin as an allosteric modulator of the spike protein of SARS-CoV-2

Alvarado, Walter; Perez-Lemus, Gustavo R.; Menéndez, Cintia A.; Byléhn, Fabian; Pablo, Juan J. de

doi:10.1039/d1me00119a

Cited by 12 publications

(16 citation statements)

References 25 publications

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“…In addition, luteolin inhibits the activities of the main protease (Chaves et al, 2022) and RNA‐dependent RNA polymerase (Munafò et al, 2022) of SARS‐CoV‐2, leading to the inhibition of viral replication in vivo. In addition to experimental reports, more than 70 articles (Alvarado et al, 2022; Shadrack et al, 2021) predicted that luteolin can interact with the S‐protein‐ACE2 complex or combine with other important proteins of SARS‐CoV‐2 by virtual screening methods. Overall, these findings suggested that luteolin is a promising natural compound for the treatment and management of SARS‐CoV‐2 infection.…”

Section: Introductionmentioning

confidence: 99%

Luteolin inhibits spike protein of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) binding to angiotensin‐converting enzyme 2

Zhu,

Yan,

Shi

et al. 2023

Phytotherapy Research

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes coronavirus disease 2019 (COVID‐19), a respiratory illness that poses a serious threat to global public health. In an essential step during infection, SARS‐CoV‐2 uses the receptor‐binding domain (RBD) of the spike (S) protein to engage with angiotensin‐converting enzyme 2 (ACE2) in host cells. Chinese herbal medicines and their active components exhibit antiviral activity, with luteolin being a flavonoid that can significantly inhibit SARS‐CoV infection. However, whether it can block the interaction between the S‐protein RBD of SARS‐CoV‐2 and ACE2 has not yet been elucidated. Here, we investigated the effects of luteolin on the binding of the S‐protein RBD to ACE2. By employing a competitive binding assay in vitro, we found that luteolin significantly blocked the binding of S‐protein RBD to ACE2 with IC50 values of 0.61 mM, which was confirmed by the neutralized infection with SARS‐CoV‐2 pseudovirus in vivo. A surface plasmon resonance‐based competition assay revealed that luteolin significantly affects the binding of the S‐protein RBD to the ACE2 receptor. Molecular docking was performed to predict the binding sites of luteolin to the S‐protein RBD‐ACE2 complex. The active binding sites were defined based on published literature, and we found that luteolin might interfere with the mixture at residues including LYS353, ASP30, and TYR83 in the cellular ACE2 receptor and GLY496, GLN498, TYR505, LEU455, GLN493, and GLU484 in the S‐protein RBD. These residues may together form attractive charges and destroy the stable interaction of S‐protein RBD‐ACE2. Luteolin also inhibits SARS‐CoV‐2 spike protein‐induced platelet spreading, thereby inhibiting the binding of the spike protein to ACE2. Our results are the first to provide evidence that luteolin is an anti‐SARS‐CoV‐2 agent associated with interference between viral S‐protein RBD‐ACE2 interactions.

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Section: Introductionmentioning

confidence: 99%

Luteolin inhibits spike protein of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) binding to angiotensin‐converting enzyme 2

Zhu,

Yan,

Shi

et al. 2023

Phytotherapy Research

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“…It represents an urgent need for an effective medical intervention strategy to avoid further social and economic consequences ( Hu et al, 2021 ). Different types of vaccines, for example, those from Pfizer-BioNTech or Moderna using the mRNA of spike (S) protein, are currently available, and there are several FDA approved drug candidates under consideration ( Li et al, 2021 ; Venkadapathi et al, 2021 ; Alvarado et al, 2022 ). At the same time, more infectious mutants such as B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), and more recently Omicron have appeared ( McCallum et al, 2021 ; Cao et al, 2022 ), and some evade from the immune system ( Yurkovetskiy et al, 2020 ; Harvey et al, 2021 ; Wang et al, 2021 ; Gobeil et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein

Dokainish¹,

Mori³

et al. 2022

eLife

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Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-EM structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down to one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.

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“…Several groups have previously identified residues important to either drug binding, allosteric effects, or both, for the S protein. According to work by Alvarado et al, LYS369 and PHE377 appeared to have important allosteric properties since binding of luteolin to these residues in the S protein induced an intense allosteric effect [13]. Verkhivker et al reported that GLU406, ASN439, LYS417 and ASN501 were centers of allosteric interactions implicated in mediating long-range communications in the binding of the S protein with ACE2 [14].…”

Section: Resultsmentioning

confidence: 99%

“…Dihedral angle values vs. time for residues identified in literature as either important to allostery or the formation of a druggable pocket: a) PHE 377 chain C phi [13], b) PHE 329 chain B psi [8], c) ASP 198 chain C psi [15], d) ASN 439 chain A psi [14]. Dihedral angle values vs. time for most other residues: e) PRO 39 chain A phi, f) ILE 332 chain B psi.…”

Section: Resultsmentioning

confidence: 99%

Time Dependent Dihedral Angle Oscillations of the Spike Protein of SARS-CoV-2 Reveal Favored Frequencies of Dihedral Angle Rotations

Bastidas

2023

Preprint

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The spike protein of SARS-CoV-2 is critical to viral infection of host cells which ultimately results in COVID-19. In this study we analyze the behavior of dihedral (phi and psi) angles of the spike protein over time from molecular dynamics and identify that the oscillations of these dihedral angles are dominated by a few discrete, relatively low frequencies in the 23-63 MHz range with 42.96875 MHz being the most prevalent frequency sampled by the oscillations. We further observe that upon tallying the populations of each individual frequency for all residues along the frequency spectrum, there is a regular alternation between high and low population counts along the increasing frequency values in the spectrum. This alternation of the counts becomes less pronounced and ultimately stabilizes as the frequency values increase. These observations thus suggest a regularity and propensity in the spike protein's dihedral angles to avoid similar oscillation population counts between vicinal frequencies. We also observe that for amino acids that are least abundant in the S protein, there are certain frequencies at which the dihedral angles never oscillate, in contrast to relatively abundant amino acids that ultimately cover the entire spectrum. This suggests that the frequency components of dihedral angle oscillations may also be a function of position in the primary structure: the more positions an amino acid is found in, the more frequencies it can sample. Lastly, certain residues identified in the literature as constituting the inside of a druggable pocket of the spike protein, as well as other residues identified as allosteric sites, are observed in our data to have distinctive time domain profiles. This motivates us to propose residues from our dynamic data, with similar time domain profiles, which may be of potential interest to the vaccine and drug design communities, for further investigation. Thus our findings indicate that there is a particular frequency domain profile for the spike protein, hidden within the time domain data, and this information, perhaps with the suggested residues, might provide additional insight into therapeutic development strategies for COVID-19 and beyond.

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Molecular characterization of COVID-19 therapeutics: luteolin as an allosteric modulator of the spike protein of SARS-CoV-2

Abstract: The interactions between the receptor binding domain (RBD) of SARS-CoV-2 and the angiotensin- converting enzyme 2 (ACE2) are crucial for viral entry and subsequent replication. Given the large and featureless...

Cited by 12 publications

References 25 publications

Luteolin inhibits spike protein of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) binding to angiotensin‐converting enzyme 2

Luteolin inhibits spike protein of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) binding to angiotensin‐converting enzyme 2

The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein

Time Dependent Dihedral Angle Oscillations of the Spike Protein of SARS-CoV-2 Reveal Favored Frequencies of Dihedral Angle Rotations

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