Effects of HIV-1 gp41-Derived Virucidal Peptides on Virus-like Lipid Membranes

Carravilla, Pablo; Cruz, Antonio; Martin-Ugarte, Itziar; Oar-Arteta, Itziar R.; Torralba, Johanna; Apellániz, Beatriz; Pérez‐Gil, Jesús; Requejo-Isidro, José; Huarte, Nerea; Nieva, José L.

doi:10.1016/j.bpj.2017.06.061

Cited by 13 publications

(13 citation statements)

References 59 publications

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“…The virucidal effect was the strongest activity observed for RcP which might suggest that an anti-CHIKV mechanism of action for this complex might be related to a direct action on the viral particle envelope. Previous studies have shown that the virucidal effect of several compounds is closely related to an action on the virus envelope (Tang et al, 1990;Schuhmacher et al, 2003;Carravilla et al, 2017;Kong et al, 2019;Russo et al, 2019). This suggests the existence of interactions between CHIKV envelope glycoproteins and RcP.…”

Section: Discussionmentioning

confidence: 93%

Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells

et al. 2020

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Chikungunya fever is a disease caused by the Chikungunya virus (CHIKV) that is transmitted by the bite of the female of Aedes sp. mosquito. The symptoms include fever, muscle aches, skin rash, and severe joint pains. The disease may develop into a chronic condition and joint pain for months or years. Currently, there is no effective antiviral treatment against CHIKV infection. Treatments based on natural compounds have been widely studied, as many drugs were produced by using natural molecules and their derivatives. Alpha-phellandrene (α-Phe) is a naturally occurring organic compound that is a ligand for ruthenium, forming the organometallic complex [Ru2Cl4(p-cymene)2] (RcP). Organometallic complexes have shown promising as candidate molecules to a new generation of compounds that presented relevant biological properties, however, there is a lack of knowledge concerning the anti-CHIKV activity of these complexes. The present work evaluated the effects of the RcP and its precursors, the hydrate ruthenium(III) chloride salt (RuCl3⋅xH2O) (Ru) and α-Phe, on CHIKV infection in vitro. To this, BHK-21 cells were infected with CHIKV-nanoluciferase (CHIKV-nanoluc), a viral construct harboring the nanoluciferase reporter gene, at the presence or absence of the compounds for 16 h. Cytotoxicity and impact on infectivity were analyzed. The results demonstrated that RcP exhibited a strong therapeutic potential judged by the selective index > 40. Antiviral effects of RcP on different stages of the CHIKV replicative cycle were investigated; the results showed that it affected early stages of virus infection reducing virus replication by 77% at non-cytotoxic concentrations. Further assays demonstrated the virucidal activity of the compound that completely blocked virus infectivity. In silico molecular docking calculations suggested different binding interactions between aromatic rings of RcP and the loop of amino acids of the E2 envelope CHIKV glycoprotein mainly through hydrophobic interactions. Additionally, infrared spectroscopy spectral analysis indicated interactions of RcP with CHIKV glycoproteins. These data suggest that RcP may act on CHIKV particles, disrupting virus entry to the host cells. Therefore, RcP may represent a strong candidate for the development of anti-CHIKV drugs.

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Section: Discussionmentioning

confidence: 93%

Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells

et al. 2020

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“…14 Thus, we next performed twophoton fluorescence imaging of Laurdan-stained GUVs to quantitatively determine lipid packing in the liposome-based vaccines that contained different amounts of Chol. 24,47 The emission spectrum of Laurdan changes in response to polarity. In a membrane context, changes in polarity are ascribed to differences in lipid packing, which influences water accessibility.…”

Section: ■ Resultsmentioning

confidence: 99%

“…GP values were calculated using in-house developed software based on MATLAB (MathWorks, MA, USA) as described in our previous papers. 24,65 After smoothing the images with a 2-pixel averaging circular filter and thresholding the intensity, GP values were calculated for every pixel on the image following eq 2,…”

Section: Functional Characterization Of Fab 10e8 and Itsmentioning

confidence: 99%

Cholesterol Constrains the Antigenic Configuration of the Membrane-Proximal Neutralizing HIV-1 Epitope

et al. 2020

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The envelope glycoprotein (Env) enables HIV-1 cell entry through fusion of host-cell and viral membranes induced by the transmembrane subunit gp41. Antibodies targeting the C-terminal sequence of the membrane-proximal external region (C-MPER) block the fusogenic activity of gp41 and achieve neutralization of divergent HIV-1 strains and isolates. Thus, recreating the structure that generates broadly neutralizing C-MPER antibodies during infection is a major goal in HIV vaccine development. Here, we have reconstituted a peptide termed CpreTM-TMD in a membrane environment. This peptide contains the C-MPER epitope and the minimum TMD residues required for the anchorage of the Env glycoprotein to the viral membrane. In addition, we have used antibody 10E8 variants to gauge the antigenic configuration attained by CpreTM-TMD as a function of the membrane cholesterol content, a functional determinant of the HIV envelope and liposome-based vaccines. Differential binding of the 10E8 variants and the trend of the IgG responses recovered from rabbits immunized with liposome-peptide formulations, suggested that cholesterol may restrict 10E8 accessibility to the C-MPER epitope. Our data ruled out the destabilization of the lipid bilayer architecture in CpreTM-TMD-containing membranes, and pointed to the perturbation of the helical conformation by lipid packing as the cause of the antigenic configuration loss induced by cholesterol. Overall, our results provide additional insights into the structural basis of the Env complex anchoring to membranes, and suggest new approaches to the design of effective immunogens directed against the near pan-neutralizing HIV-1 epitope C-MPER.

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“…With 50% cholesterol, IWYIK was found to decrease the bilayer repeat distance, while LWYIK increased it [106]. There is evidence that longer peptides containing LWYIK may act as inhibitors of HIV fusion activity [107]. It was found that deletion of LWYIK from the gp41 fusion protein resulted in a fusion inactive virus [108] ; however, this study provided evidence that this segment was needed for the enlargement of fusion pores and for post-fusion activity, rather than for interaction with cholesterol and rafts.…”

Section: Role Of Cholesterol In Membrane Fusionmentioning

confidence: 97%

Cholesterol-Recognition Motifs in Membrane Proteins

Fantini

Epand

Barrantes

2019

Advances in Experimental Medicine and Biology

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The impact of cholesterol on the structure and function of membrane proteins was recognized several decades ago, but the molecular mechanisms underlying these effects have remained elusive. There appear to be multiple mechanisms by which cholesterol interacts with proteins. A complete understanding of these motifs is still undergoing refinement. Initially, cholesterol was thought to exert only non-specific effects on membrane fluidity. It was later shown that this lipid could specifically interact with membrane proteins and affect both their structure and function. In this article, we have summarized and critically analyzed our evolving understanding of the affinity, specificity and stereoselectivity of the interactions of cholesterol with membrane proteins. We review the different computational approaches that are currently used to identify cholesterol binding sites in membrane proteins and the biochemical logic that governs each type of site, including CRAC, CARC, SSD and amphipathic helix motifs. There are physiological implications of these cholesterolrecognition motifs for G-protein coupled receptors (GPCR) and ion channels, in membrane trafficking and membrane fusion (SNARE) proteins. There are also pathological implications of cholesterol binding to proteins involved in neurological disorders (Alzheimer, Parkinson, Creutzfeldt-Jakob) and HIV fusion. In each case, our discussion is focused on the key molecular aspects of the cholesterol and amino acid motifs in membrane-embedded regions of membrane proteins that define the physiologically relevant crosstalk between the two. Our understanding of the factors that determine if these motifs are functional in cholesterol binding will allow us enhanced predictive ability.

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Effects of HIV-1 gp41-Derived Virucidal Peptides on Virus-like Lipid Membranes

Cited by 13 publications

References 59 publications

Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells

Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells

Cholesterol Constrains the Antigenic Configuration of the Membrane-Proximal Neutralizing HIV-1 Epitope

Cholesterol-Recognition Motifs in Membrane Proteins

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