Biology subjects

Ostroumova, O. S.

Publications and source records attributed to Ostroumova, O. S..

4 recordsLinked to original sources

bioRxiv2024

Lipid specificity of action of SARS-CoV-2 fusion peptide fragments on model membranes

The study focuses on investigating the interaction of SARS-CoV-2 fusion peptide fragment with model membranes of various lipid composition to elucidate the molecular mechanisms of peptide-derived membrane fusion. The work utilized the short fragment of SARS-CoV-2 fusion peptide which is homologous to 816-827 region of the native SARS-CoV-2 FP (FP816-827) and contains the highly conserved LLF motif responsible for membrane fusion, and its ineffective analogue (mFP816-827), where LLF motif was replaced for AAA. Using fluorescence fusion assay, it was demonstrated that the LLF motif plays a key role in inducing liposome fusion, whereas its replacement completely abolishes this capability. The fusogenic activity of the peptide strictly depended on the vesicle lipid composition. It was potentiated by phosphatidylethanolamine and inhibited by phosphatidylserine. Molecular dynamics revealed that both peptides predominantly adopt an -helical conformation; however, the native peptide interacts more strongly with the hydrophobic core of the membrane by increasing peptide-lipid hydrophobic contacts, while the mutant version exhibits a more superficial localization. Differential scanning microcalorimetry data indicated that the ability of FP816- 827 to disturb lipid packing increased with decreasing membrane lipid tail length. The molecular mechanisms underlying the fusogenic activity of the SARS-CoV-2 fusion peptide were identified, specifically its ability to cluster phospholipid head groups in its own vicinity. As a result, local regions with positive spontaneous curvature are formed in the outer monolayer, facilitating membrane fusion. The findings highlight the role of membrane composition and lipid architecture in the mechanism of viral fusion with host cells.

biophysics↗

bioRxiv2024

Echinocandins have an alternative mode of action on biomimetic membranes that is not directly related to the functioning of (1,3) beta-glucan synthase

Echinocandins, one of five main classes of antifungal agents, are FDA-approved drugs for therapy of invasive candidiasis and aspergillosis. The exact mechanisms of echinocandins action are still under debates, in particular the role of target cell membranes in their function. In present study we analyzed the molecular mechanisms of action of echinocandins (anidulafungin, caspofungin, and micafungin) on the sterol-enriched lipid bilayers mimicking fungal and mammalian membranes. Calcein release assay and molecular dynamics simulations demonstrated the relation of the membrane permeability and echinocandin type. Moreover, we have shown for the first time the ability of echinocandins to form ion-permeable pores in sterol-containing membranes. Differential scanning microcalorimetry of the gel-to-liquid-crystalline lipid phase transition and confocal fluorescent microscopy of lipid domains revealed the ability of echinocandins to enhance phase segregation in membrane. Thus, echinocandins might affect the (1,3) beta-glucan synthase functioning by alteration in lipid microenvironment of target protein and cellular membrane permeability via formation of ion-selective leakage channels. We also found that small natural molecule, phloretin, potentiated the pore-forming activity of micafungin in the ergosterol-containing bilayers and significantly reduced the minimum inhibitory concentration of micafungin against fluconazole-resistant Candida albicans, C. tropicalis, and C.krusei.

microbiology↗

bioRxiv2022

Cyclic lipopeptides as membrane fusion inhibitors against SARS-CoV-2: new tricks for old dogs

With the resurgence of the coronavirus pandemic, the repositioning of FDA-approved drugs against coronovirus and finding alternative strategies for antiviral therapy are both important. We previously identified the viral lipid envelope as a potential target for the prevention and treatment of SARS-CoV-2 infection with plant alkaloids [1]. Here, we investigated the effects of eleven cyclic lipopeptides (CLPs), including well-known antifungal and antibacterial compounds, on the liposome fusion triggered by calcium, polyethylene glycol 8000, and a fragment of SARS-CoV-2 fusion peptide (816-827) by calcein release assays. Differential scanning microcalorimetry of the gel-to-liquid-crystalline and lamellar-to-inverted hexagonal phase transitions and confocal fluorescence microscopy demonstrated the relation of the fusion inhibitory effects of CLPs to alterations in lipid packing, membrane curvature stress and domain organization. The effects of the compounds were evaluated in an in vitro Vero-based cell model, and aculeacin A, anidulafugin, iturin A, and mycosubtilin attenuated the cytopathogenicity of SARS-CoV-2 without specific toxicity.

molecular biology↗

bioRxiv2019

Soluble cyanobacterial carotenoprotein as a robust antioxidant nanocarrier and delivery module

To counteract oxidative stress, antioxidants including carotenoids are highly promising, yet their exploitation is drastically limited by the poor bioavailability and fast photodestruction, whereas current delivery systems are far from being efficient. Here we demonstrate that the recently discovered nanometer-sized water-soluble carotenoprotein from Anabaena (termed CTDH) transiently interacts with liposomes to efficiently extract carotenoids via carotenoid-mediated homodimerization, yielding violet-purple protein samples amenable to lyophilization and long-term storage. We characterize spectroscopic properties of the pigment-protein complexes and thermodynamics of liposome-protein carotenoid transfer and demonstrate the highly efficient delivery of echinenone form CTDH into liposomes. Most importantly, we show carotenoid delivery to membranes of mammalian cells, which provides protection from reactive oxygen species. The described carotenoprotein may be considered as part of modular systems for the targeted antioxidant delivery.\n\nSignificance statementCarotenoids are excellent natural antioxidants but their delivery to vulnerable cells is challenging due to their hydrophobic nature and susceptibility to degradation. Thus, systems securing antioxidant stability and facilitating targeted delivery are of great interest for the design of medical agents. In this work, we have demonstrated that soluble cyanobacterial carotenoprotein can deliver echinenone into membranes of liposomes and mammalian cells with almost 70 % efficiency, which alleviates the induced oxidative stress. Our findings warrant the robustness of the protein-based carotenoid delivery for studies of carotenoid activities and effects on cell models.

biophysics↗