“…While about 12 such motifs are found in NTD, only one exists in the RBD. [46] , [65] Therefore, cholesterol preferentially binds to NTD sub- domain that is consistent with our data shown in Table 2 . Figure 5 The average residence time per residue of different surfactants on S1 at different surfactant concentrations .…”
“…While about 12 such motifs are found in NTD, only one exists in the RBD. [46] , [65] Therefore, cholesterol preferentially binds to NTD sub- domain that is consistent with our data shown in Table 2 . Figure 5 The average residence time per residue of different surfactants on S1 at different surfactant concentrations .…”
“…In our cell–cell fusion assay, depletion of plasma membrane CHOL in the presence of MβCD induced a dramatic (∼70%) decrease of fusion between the cells expressing S proteins and the cells expressing ACE2 receptors (Figure ). This agrees well with two recent studies which found that efficient SARS-CoV-2 fusion with the cell membrane requires CHOL, , and with the fact that several CHOL-recognition motifs have been identified in various regions of the S protein, including the FP1 domain . Interestingly, the effect of CHOL on FP1-mediated liposome fusion was only observed when PE was also present in the membrane (Figures and S2).…”
SARS-CoV-2 entry into host cells is mediated by the Spike
(S) protein
of the viral envelope. The S protein is composed of two subunits:
S1 that induces binding to the host cell
via
its
interaction with the ACE2 receptor of the cell surface and S2 that
triggers fusion between viral and cellular membranes. Fusion by S2
depends on its heptad repeat domains that bring membranes close together
and its fusion peptide (FP) that interacts with and perturbs the membrane
structure to trigger fusion. Recent studies have suggested that cholesterol
and ceramide lipids from the cell surface may facilitate SARS-CoV-2
entry into host cells, but their exact mode of action remains unknown.
We have used a combination of
in vitro
liposome–liposome
and
in situ
cell–cell fusion assays to study
the lipid determinants of S-mediated membrane fusion. Our findings
reveal that both cholesterol and ceramide lipids facilitate fusion,
suggesting that targeting these lipids could be effective against
SARS-CoV-2. As a proof of concept, we examined the effect of chlorpromazine
(CPZ), an antipsychotic drug known to perturb membrane structure.
Our results show that CPZ effectively inhibits S-mediated membrane
fusion, thereby potentially impeding SARS-CoV-2 entry into the host
cell.
“…Furthermore, and comparing the number of contacts between the FP and all the lipids with those of POPC, the major lipid in the membrane, the number of contacts was significantly higher for BMGP but much lower for CHOL, showing that the FP would tend to bind preferentially negatively-charged phospholipids but would exclude CHOL. It is interesting to note that it has been described that the FP from SARS-CoV-2 possess two CHOL-recognition motifs, which could suggest that FP could bind with CHOL at some point in the fusion process [ 27 ]. It could be possible that the first step in the fusion process would be the specific interaction of the FP with certain types of phospholipids and subsequently interact with the deepest part of the membrane where cholesterol resides.…”
Section: Discussionmentioning
confidence: 99%
“…Since one of the most important characteristics of the negatively-charged phospholipids is their charged headgroup, it can be implicitly supposed that the most important binding force should be of an electrostatic nature. However, that is not the only feature involved in the binding process since there are several hydrophobic amino acids surrounding the basic and acidic ones, i.e., Leu, Phe, Val, Ile and Ala residues, which can establish a large number of contacts with the phospholipid as well as cholesterol [ 21 , 26 , 27 ]. It can be concluded that the membrane driving force is a combination of charged and hydrophobic residues, dividing the task to interact with the membrane on the one hand and specifically interacting with the electronegatively charged phospholipids on the other.…”
Section: Discussionmentioning
confidence: 99%
“…The SARS-CoV-2 FP modulates the membrane dynamics, decreasing the fluidity of phospholipids, a phenomenon seeming to be modulated by the presence of Ca 2+ [ 19 , 20 , 25 , 26 ]. Interestingly, the FP from SARS-CoV-2 possesses two CHOL-recognition motifs, suggesting that it could bind CHOL at some point in the fusion process [ 27 ]. Both FP1 and FP2 seem to be necessary for fusion to take place [ 17 , 25 ].…”
COVID-19, caused by SARS-CoV-2, which is a positive-sense, single-stranded RNA enveloped virus, emerged in late 2019 and was declared a worldwide pandemic in early 2020 causing more than 600 million infections so far and more than 6 million deaths in the world. Although new vaccines have been implemented, the pandemic continues to impact world health dramatically. Membrane fusion, critical for the viral entry into the host cell, is one of the main targets for the development of novel antiviral therapies to combat COVID-19. The S2 subunit of the viral S protein, a class I membrane fusion protein, contains the fusion domain which is directly implicated in the fusion mechanism. The knowledge of the membrane fusion mechanism at the molecular level will undoubtedly result in the development of effective antiviral strategies. We have used all-atom molecular dynamics to analyse the binding of the SARS-CoV-2 fusion peptide to specific phospholipids in model membranes composed of only one phospholipid plus cholesterol in the presence of either Na+ or Ca2+. Our results show that the fusion peptide is capable of binding to the membrane, that its secondary structure does not change significantly upon binding, that it tends to preferentially bind electronegatively charged phospholipids, and that it does not bind cholesterol at all. Understanding the intricacies of the membrane fusion mechanism and the molecular interactions involved will lead us to the development of antiviral molecules that will allow a more efficient battle against these viruses.
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