Cholesterol-Enriched Domain Formation Induced by Viral-Encoded, Membrane-Active Amphipathic Peptide

Hanson, Joshua M.; Gettel, Douglas L.; Tabaei, Seyed R.; Jackman, Joshua A.; Kim, Min Chul; Sasaki, Darryl Y.; Groves, Jay T.; Liedberg, Bo; Cho, Nam‐Joon; Parikh, Atul N.

doi:10.1016/j.bpj.2015.11.032

Cited by 22 publications

(15 citation statements)

References 64 publications

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“…The AH peptide has also been shown to target HIV and measles, which have sizes ranging from 100 to 150 nm, indicating that the composition of the virus may also play a role in the antiviral capabilities of this peptide [ 54 ]. It has been found to target viral envelopes with a higher cholesterol content, so viruses such as West Nile virus and dengue virus are prime targets [ 53 , 55 ]. Both viruses bud into the endoplasmic reticulum and have a naturally cholesterol-enriched envelope.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Nanotechnology for virus treatment

et al. 2021

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Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Nanotechnology for virus treatment

et al. 2021

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“…Model membranes composed of well-defined synthetic lipids are useful tools for studying questions related to membrane biology (10,11). The importance of lipid remodeling in biology underscores the need for straightforward methods to remodel lipid composition in artificial model membranes.…”

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confidence: 99%

Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes

Brea

Rudd

Devaraj

2016

Proc. Natl. Acad. Sci. U.S.A.

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Cell membranes have a vast repertoire of phospholipid species whose structures can be dynamically modified by enzymatic remodeling of acyl chains and polar head groups. Lipid remodeling plays important roles in membrane biology and dysregulation can lead to disease. Although there have been tremendous advances in creating artificial membranes to model the properties of native membranes, a major obstacle has been developing straightforward methods to mimic lipid membrane remodeling. Stable liposomes are typically kinetically trapped and are not prone to exchanging diacylphospholipids. Here, we show that reversible chemoselective reactions can be harnessed to achieve nonenzymatic spontaneous remodeling of phospholipids in synthetic membranes. Our approach relies on transthioesterification/ acyl shift reactions that occur spontaneously and reversibly between tertiary amides and thioesters. We demonstrate exchange and remodeling of both lipid acyl chains and head groups. Using our synthetic model system we demonstrate the ability of spontaneous phospholipid remodeling to trigger changes in vesicle spatial organization, composition, and morphology as well as recruit proteins that can affect vesicle curvature. Membranes capable of chemically exchanging lipid fragments could be used to help further understand the specific roles of lipid structure remodeling in biological membranes.L iving organisms carry out the de novo synthesis of phospholipid membranes, in part, by using membrane-bound acyltransferases and reactive thioester precursors ( Fig. 1A) (1). Subsequently, de novo synthesized phospholipid membranes can be remodeled by acyltransferases and transacylases in the presence of different lysolipid, phospholipid, and fatty acid precursors ( Fig. 1A) (2). Such natural mechanisms allow cells to fine-tune properties of biological membranes by changing the composition and organization of their constituent lipids and proteins (3). Membrane remodeling is an essential component of numerous cellular functions including the formation of organelles (4), division (5), trafficking (6), and signaling (7). Many experimental and theoretical studies have examined membrane remodeling due to enzymatically driven changes in lipid composition (8). For instance, the disruption of the transacylase activity of the enzyme tafazzin leads to alterations in the mitochondrial lipid cardiolipin and the disease known as Barth's syndrome (9).Model membranes composed of well-defined synthetic lipids are useful tools for studying questions related to membrane biology (10, 11). The importance of lipid remodeling in biology underscores the need for straightforward methods to remodel lipid composition in artificial model membranes. Unfortunately, nonenzymatic methods to exchange lysolipid fragments in synthetic vesicles have previously not been feasible. This is likely due to the high kinetic stability of phospholipid membranes, which do not readily exchange diacylphospholipid species between membranes (12). Because the composition of phospholipids c...

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“…For example, CRAC motifs are present in the HIV matrix protein р17, which was shown to participate in virus entry through the raft domains of the cell membranes [27,101]. The α-helical domain of the hepatitis C virus nonstructural protein NS5A, which is anchored at the cytoplasmic leaflet of the endoplasmic reticulum and is involved in replication hepatitis C virus, also contains CRAC motif [102]. Importantly, peptides derived from this domain were shown to exhibit a broad-spectrum anti-viral activity.…”

Section: Cholesterol Recognition/interaction Amino Acid Consensus (Crmentioning

confidence: 99%

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

Dunina-Barkovskaya¹

2021

Management of Dyslipidemia

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Some interactions of enveloped viruses with the host cell membrane have a cholesterol-dependent component, which may account for clinical manifestations of the infectious disease and can be used for the development of antiviral drugs. These cholesterol-dependent interactions can be mediated by cholesterol-recognition amino-acid consensus (CRAC) motifs present in viral proteins. The S protein of the SARS-CoV and SARS-CoV2 coronaviruses contains CRAC motifs that can be involved in the process of virus entry into the cell. Besides, during viral envelope formation, CRAC motifs can be responsible for binding of cell membrane cholesterol, leading to depletion of cell membrane cholesterol and subsequent malfunctioning of cellular cholesterol-dependent proteins, destabilization and permeabilization of cell membranes and, ultimately, to the death of infected cells. Understanding the mechanisms of cholesterol-dependent virus–cell interactions and the role of CRAC-containing viral proteins in the pathogenesis of the disease can serve as the basis for the development of new drugs that prevent both coronavirus entry into the cell and the damage of the infected cell during the viral morphogenesis. The target for such drugs can be the S-protein/cholesterol interface. CRAC-containing peptides derived from viral proteins may be among these agents. These peptides can also be used as experimental tools to study cholesterol-dependent virus–cell interactions.

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Cholesterol-Enriched Domain Formation Induced by Viral-Encoded, Membrane-Active Amphipathic Peptide

Cited by 22 publications

References 64 publications

Nanotechnology for virus treatment

Nanotechnology for virus treatment

Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

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