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1.

001-es BibID:BIBFORM110635
035-os BibID:(WoS)000985072100001 (Scopus)85151447550
Első szerző:Kovács Tamás (általános orvos)
Cím:Veklury (remdesivir) formulations inhibit initial membrane-coupled events of SARS-CoV-2 infection due to their sulfobutylether-β-cyclodextrin content / Kovacs Tamas, Kurtan Kitti, Varga Zoltan, Nagy Peter, Panyi Gyorgy, Zakany Florina
Dátum:2023
ISSN:0007-1188
Megjegyzések:Background and Purpose: Despite its contradictory clinical performance, remdesivir (Veklury®) has a pivotal role in COVID-19 therapy. Possible contributions of the vehicle, sulfobutylether-β-cyclodextrin (SBECD) to Veklury® effects have been overlooked. The powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane-coupled events of SARS-CoV-2 infection focusing on the cholesterol depletion-mediated role of SBECD. Experimental Approach: Using time-correlated flow cytometry and quantitative three-dimensional confocal microscopy, we studied early molecular events of SARS-CoV-2?host cell membrane interactions. Key Results: Veklury® and different cholesterol-depleting cyclodextrins (CDs) reduced binding of the spike receptor-binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan-Hu-1, Delta and Omicron variants. Correlations of these effects with cholesterol-dependent changes in membrane structure and decreased lipid raft-dependent ACE2-TMPRSS2 interaction establish that SBECD is not simply a vehicle but also an effector along with remdesivir due to its cholesteroldepleting potential. Veklury® solution inhibited RBD binding more efficiently due to its twice higher SBECD content. The CD-induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression, indicating that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low. Conclusion and Implications: Our findings call for the differentiation of Veklury® formulations in meta-analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant cyclodextrin (CD) therapy, even at higher doses, in COVID-19.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
cholesterol
cyclodextrin
remdesivir
SARS-CoV-2
spike glycoprotein
Megjelenés:British Journal Of Pharmacology. - 180 : 16 (2023), p. 2064-2084. -
További szerzők:Kurtán Kitti Varga Zoltán (1969-) (biofizikus, szakfordító) Nagy Péter (1971-) (biofizikus) Panyi György (1966-) (biofizikus) Zákány Florina (1989-) (általános orvos)
Pályázati támogatás:ANN133421
OTKA
OTKA FK143400
OTKA
K132906
OTKA
K138075
OTKA
K143071
OTKA
UNKP-21-4-II-DE- 137
Egyéb
UNKP-21-4-II-DE-138
Egyéb
EFOP-3.6.2-16-2017-00006
Egyéb
GINOP-2.3.2-15-2016-00015
Egyéb
UNKP-22-4-II-DE-69
Egyéb
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2.

001-es BibID:BIBFORM105453
035-os BibID:(cikkazonosító)2559 (WOS)000904144700001 (Scopus)85144901772
Első szerző:Kovács Tamás (általános orvos)
Cím:Cyclodextrins : Only Pharmaceutical Excipients or Full-Fledged Drug Candidates? / Kovacs Tamas, Nagy Peter, Panyi Gyorgy, Szente Lajos, Varga Zoltan, Zakany Florina
Dátum:2022
ISSN:1999-4923
Megjegyzések:Cyclodextrins, representing a versatile family of cyclic oligosaccharides, have extensive pharmaceutical applications due to their unique truncated cone-shaped structure with a hydrophilic outer surface and a hydrophobic cavity, which enables them to form non-covalent host?guest inclusion complexes in pharmaceutical formulations to enhance the solubility, stability and bioavailability of numerous drug molecules. As a result, cyclodextrins are mostly considered as inert carriers during their medical application, while their ability to interact not only with small molecules but also with lipids and proteins is largely neglected. By forming inclusion complexes with cholesterol, cyclodextrins deplete cholesterol from cellular membranes and thereby influence protein function indirectly through alterations in biophysical properties and lateral heterogeneity of bilayers. In this review, we summarize the general chemical principles of direct cyclodextrin?protein interactions and highlight, through relevant examples, how these interactions can modify protein functions in vivo, which, despite their huge potential, have been completely unexploited in therapy so far. Finally, we give a brief overview of disorders such as Niemann?Pick type C disease, atherosclerosis, Alzheimer's and Parkinson's disease, in which cyclodextrins already have or could have the potential to be active therapeutic agents due to their cholesterol-complexing or direct protein-targeting properties.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Pharmaceutics. - 14 (2022), p. 1-38. -
További szerzők:Nagy Péter (1971-) (biofizikus) Panyi György (1966-) (biofizikus) Szente Lajos (1951-) (vegyész) Varga Zoltán (1969-) (biofizikus, szakfordító) Zákány Florina (1989-) (általános orvos)
Pályázati támogatás:ANN133421
OTKA
K138075
OTKA
FK143400
OTKA
K143071
OTKA
K132906
OTKA
UNKP?22?4?II?DE?69
Egyéb
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM097599
035-os BibID:(cikkazonosító)735357
Első szerző:Kovács Tamás (általános orvos)
Cím:Cyclodextrins exert a ligand-like current inhibitory effect on the KV1.3 ion channel independent of membrane cholesterol extraction / Tamas Kovacs, Tamas Sohajda, Lajos Szente, Peter Nagy, Gyorgy Panyi, Zoltan Varga, Florina Zakany
Dátum:2021
Megjegyzések:Cyclodextrins (CDs) are cyclic oligosaccharides capable of forming water-soluble complexes with a variety of otherwise poorly soluble molecules including cholesterol and different drugs. Consistently, CDs are widely used in research and clinical practice to deplete cholesterol from cellular membranes or to increase solubility and bioavailability of different pharmaceuticals at local concentrations in the millimolar range. Effects of CDs exerted on cellular functions are generally thought to originate from reductions in cholesterol levels. Potential direct, ligand-like CD effects are largely neglected in spite of several recent studies reporting direct interaction between CDs and proteins including AMP activated protein kinase, ?-amyloid peptides, and ?-synuclein. In this study, by using patch-clamp technique, time-resolved quantitation of cholesterol levels and biophysical parameters and applying cholesterol-extracting and non-cholesterol-extracting CDs at 1 and 5 mM concentrations, we provide evidence for a previously unexplored ligand-like, cholesterol-independent current inhibitory effect of CDs on KV1.3, a prototypical voltage-gated potassium channel with pathophysiological relevance invarious autoimmune and neurodegenerative disorders. Our findings propose that potential direct CD effects on KV channels should be taken into consideration when interpreting functional consequences of CD treatments in both research and clinical practice. Furthermore, current-blocking effects of CDs on KV channels at therapeutically relevant concentrations might contribute to additional beneficial or adverse effects during their therapeutic applications.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
cyclodextrin
ligand-like interaction
membrane lipid order
membrane hydration
membrane fluidity
cholesterol
KV1.3
Megjelenés:Frontiers in Molecular Biosciences. - 8 (2021), p. 1-11. -
További szerzők:Sohajda Tamás Szente Lajos (1951-) (vegyész) Nagy Péter (1971-) (biofizikus) Panyi György (1966-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító) Zákány Florina (1989-) (általános orvos)
Pályázati támogatás:UNKP-19-3-III-DE-92
Egyéb
UNKP-21-4-II-DE-138
Egyéb
UNKP-21-4-II-DE-137
Egyéb
NTP-NFTÖ-20-B-0115
Egyéb
EFOP-3.6.1-16-2016-00022
EFOP
GINOP-2.3.2-15-2016-00044
GINOP
OTKA K132906
OTKA
SNN139532
OTKA
K119417
OTKA
ANN133421
OTKA
2019-2.1.11-TÉT-2019-00059
Egyéb
2020-1.1.2-PIACI-KFI-2020-00092
Egyéb
Internet cím:DOI
Intézményi repozitóriumban (DEA) tárolt változat
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4.

001-es BibID:BIBFORM005107
Első szerző:Vámosi György (biofizikus)
Cím:The role of supramolecular protein complexes and membrane potential in transmembrane signaling processes of lymphocytes / Vamosi, G., Bodnar, A., Damjanovich, S., Nagy, P., Varga, Z., Damjanovich, L.
Dátum:2006
ISSN:165-2478 (Print)
Megjegyzések:The formation of protein patterns in lymphocyte plasma membranes is analyzed in the light of past and, also, very recent experiments. The analysis surveys the lateral organization of major histocompatibility complex glycoproteins, intercellular adhesion molecule-1, interleukin-2 and -15 receptors, Kv1.3 K+ ion channels and the T-cell receptor as well as their behavior under different conditions. These molecules form small- and large-scale clusters in the membrane of human lymphocytes. Many of the association motifs occur in other investigated cell types. The conclusions point toward a possible role for ion channel activities, membrane potential changes and alterations of the lateral organization of proteins in transmembrane signaling and cytotoxic interactions. In our outlook new factors that potentially affect membrane protein cluster formation and interactions are discussed. A role for MHC glycoproteins in concentrating membrane proteins and organizing protein patterns is suggested, and the possibility that the membrane potential may modulate protein conformation and, thereby, affect protein-protein interactions is pointed out. A well-defined role for the presence of ion channels in the immune synapse is offered, which could explain the significance of ion channel accumulation in the immune synapse together with the T-cell receptor.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
analysis
Animals
Biophysics
Cell Membrane
Glycoproteins
Human
Humans
Hungary
immunology
Intercellular Adhesion Molecule-1
Interleukin-2
Ion Channels
Light
Lymphocytes
Major Histocompatibility Complex
Membrane Potentials
Membrane Proteins
metabolism
Multiprotein Complexes
physiology
Protein Conformation
Proteins
Research
Signal Transduction
Support
T-Lymphocytes
Megjelenés:Immunology Letters. - 104 : 1-2 (2006), p. 53-58. -
További szerzők:Dóczy-Bodnár Andrea (1970-) (biofizikus) Damjanovich Sándor (1936-2017) (biofizikus) Nagy Péter (1971-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító) Damjanovich László (1960-) (általános sebész)
Internet cím:DOI
elektronikus változat
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5.

001-es BibID:BIBFORM112909
035-os BibID:(cikkazonosító)1700 (WoS)001030946800001 (Scopus)85164845617
Első szerző:Zákány Florina (általános orvos)
Cím:Effect of the Lipid Landscape on the Efficacy of Cell-Penetrating Peptides / Zakany Florina, Mándity István M., Varga Zoltan, Panyi Gyorgy, Nagy Peter, Kovacs Tamas
Dátum:2023
ISSN:2073-4409
Megjegyzések:Every cell biological textbook teaches us that the main role of the plasma membrane is to separate cells from their neighborhood to allow for a controlled composition of the intracellular space. The mostly hydrophobic nature of the cell membrane presents an impenetrable barrier for most hydrophilic molecules larger than 1 kDa. On the other hand, cell-penetrating peptides (CPPs) are capable of traversing this barrier without compromising membrane integrity, and they can do so on their own or coupled to cargos. Coupling biologically and medically relevant cargos to CPPs holds great promise of delivering membrane-impermeable drugs into cells. If the cargo is able to interact with certain cell types, uptake of the CPP?drug complex can be tailored to be cell-typespecific.Besides outlining the major membrane penetration pathways of CPPs, this review is aimed at deciphering how properties of the membrane influence the uptake mechanisms of CPPs. By summarizing an extensive body of experimental evidence, we argue that a more ordered, less flexible membrane structure, often present in the very diseases planned to be treated with CPPs, decreases their cellular uptake. These correlations are not only relevant for understanding the cellular biology of CPPs, but also for rationally improving their value in translational or clinical applications.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
sejtpenetráló peptidek
sejtmembrán
lipidek
Megjelenés:Cells. - 12 : 13 (2023), p. 1-29. -
További szerzők:Mándity István M. Varga Zoltán (1969-) (biofizikus, szakfordító) Panyi György (1966-) (biofizikus) Nagy Péter (1971-) (biofizikus) Kovács Tamás (1985-) (általános orvos)
Pályázati támogatás:FK143400
OTKA
K138075
OTKA
ANN133421
OTKA
K132906
OTKA
ANN 139484
OTKA
K139216
OTKA
K143071
OTKA
Internet cím:Szerző által megadott URL
DOI
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6.

001-es BibID:BIBFORM093476
035-os BibID:(cikkazonosító)647300
Első szerző:Zákány Florina (általános orvos)
Cím:An [omega]-3, but Not an [omega]-6 Polyunsaturated Fatty Acid Decreases Membrane Dipole Potential and Stimulates Endo-Lysosomal Escape of Penetratin / Zakany Florina, Szabo Mate, Batta Gyula, Kárpáti Levente, Mándity István M., Fülöp Péter, Varga Zoltan, Panyi Gyorgy, Nagy Peter, Kovacs Tamas
Dátum:2021
ISSN:2296-634X 2296-634X
Megjegyzések:Although the largely positive intramembrane dipole potential (DP) may substantially influence the function of transmembrane proteins, its investigation is deeply hampered by the lack of measurement techniques suitable for high-throughput examination of living cells. Here, we describe a novel emission ratiometric flow cytometry method based on F66, a 3-hydroxiflavon derivative, and demonstrate that 6-ketocholestanol, cholesterol and 7-dehydrocholesterol, saturated stearic acid (SA) and &-6 g-linolenic acid (GLA) increase, while &-3 a-linolenic acid (ALA) decreases the DP. These changes do not correlate with alterations in cell viability or membrane fluidity. Pretreatment with ALA counteracts, while SA or GLA enhances cholesterol-induced DP elevations. Furthermore, ALA (but not SA or GLA) increases endo-lysosomal escape of penetratin, a cell-penetrating peptide. In summary, we have developed a novel method to measure DP in large quantities of individual living cells and propose ALA as a physiological DP lowering agent facilitating cytoplasmic entry of penetratin.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
membrane dipole potential
polyunsaturated fatty acids
cholesterol
penetratin
flow cytometry
Megjelenés:Frontiers in Cell and Developmental Biology. - 9 (2021), p. 1-17. -
További szerzők:Szabó Máté Batta Gyula (1979-) (biológus) Kárpáti Levente (1968-) (okleveles vegyész) Mándity István M. Fülöp Péter (1974-) (belgyógyász, endokrinológus, lipidológus) Varga Zoltán (1969-) (biofizikus, szakfordító) Panyi György (1966-) (biofizikus) Nagy Péter (1971-) (biofizikus) Kovács Tamás (1985-) (általános orvos)
Pályázati támogatás:K120302
OTKA
ANN133421
OTKA
GINOP-2.3.2-15-2016-00020
GINOP
GINOP-2.3.2-15-2016-00044
GINOP
K132906
OTKA
TÉT - 2019 ? 2.1.11-TÉT-2019- 00059
Egyéb
K119417
OTKA
GINOP-2.3.2-15-2016-00015
GINOP
2018-1.2.1-NKP-2018-00005
Egyéb
UNKP-19-3-III-DE-92
Egyéb
NTP-NFTÖ-20-B-0115
Egyéb
MTA-DE Lendület
MTA
Matematikai és természettudományok - Kémiai tudományok
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7.

001-es BibID:BIBFORM077302
Első szerző:Zákány Florina (általános orvos)
Cím:Determining the target of membrane sterols on voltage-gated potassium channels / Florina Zakany, Pal Pap, Ferenc Papp, Tamas Kovacs, Peter Nagy, Maria Peter, Lajos Szente, Gyorgy Panyi, Zoltan Varga
Dátum:2019
ISSN:1388-1981
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Biochimica et Biophysica Acta (BBA). Molecular and Cell Biology of Lipids. - 1864 : 3 (2019), p. 312-325. -
További szerzők:Pap Pál (1981-) (élettanász) Papp Ferenc (1979-) (biofizikus) Kovács Tamás (1985-) (általános orvos) Nagy Péter (1971-) (biofizikus) Péter Mária Szente Lajos (1951-) (vegyész) Panyi György (1966-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító)
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