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001-es BibID:BIBFORM090877
035-os BibID:(cikkazonosító)1183 (scopus)85099978064 (wos)000615359000001
Első szerző:Czajlik András (gyógyszerész)
Cím:Solution Structure, Dynamics, and New Antifungal Aspects of the Cysteine-Rich Miniprotein PAFC / András Czajlik, Jeanett Holzknecht, László Galgóczy, Liliána Tóth, Péter Poór, Attila Ördög, Györgyi Váradi, Alexander Kühbacher, Attila Borics, Gábor K. Tóth, Florentine Marx, Gyula Batta
Dátum:2021
ISSN:1661-6596 1422-0067
Megjegyzések:The genome of Penicillium chrysogenum Q176 contains a gene coding for the 88-amino-acid (aa)-long glycine- and cysteine-rich P. chrysogenum antifungal protein C (PAFC). After maturation, the secreted antifungal miniprotein (MP) comprises 64 aa and shares 80% aa identity with the bubble protein (BP) from Penicillium brevicompactum, which has a published X-ray structure. Our team expressed isotope (15N, 13C)-labeled, recombinant PAFC in high yields, which allowed us to determine the solution structure and molecular dynamics by nuclear magnetic resonance (NMR) experiments. The primary structure of PAFC is dominated by 14 glycines, and therefore, whether the four disulfide bonds can stabilize the fold is challenging. Indeed, unlike the few published solution structures of other antifungal MPs from filamentous ascomycetes, the NMR data indicate that PAFC has shorter secondary structure elements and lacks the typical ??-barrel structure, though it has a positively charged cavity and a hydrophobic core around the disulfide bonds. Some parts within the two putative ??-core motifs exhibited enhanced dynamics according to a new disorder index presentation of 15N-NMR relaxation data. Furthermore, we also provided a more detailed insight into the antifungal spectrum of PAFC, with specific emphasis on fungal plant pathogens. Our results suggest that PAFC could be an effective candidate for the development of new antifungal strategies in agriculture.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Penicillium chrysogenum
antifungal protein PAFC
γ-core motif
solution structure
dynamics
nuclear magnetic resonance
plant protection
Megjelenés:International Journal of Molecular Sciences. - 22 : 3 (2021), p. 1-23. -
További szerzők:Holzknecht, Jeanett Galgóczy László (1950-) Tóth Liliána Poór Péter Ördög Attila Váradi Györgyi Kühbacher, Alexander Borics Attila Tóth Gábor K. Marx, Florentine Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:NKFIH FK 134343
Egyéb
NKFIH PD 134284
Egyéb
GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
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2.

001-es BibID:BIBFORM072756
035-os BibID:(cikkazonosító)393 (WOS)000426785800002 (Scopus)85043257197
Első szerző:Tóth Liliána
Cím:Anti-Candidal Activity and Functional Mapping of Recombinant and Synthetic Neosartorya fischeri Antifungal Protein 2 (NFAP2) / Tóth Liliána, Váradi Györgyi, Borics Attila, Batta Gyula, Kele Zoltán, Vendrinszky Ákos, Tóth Roberta, Ficze Hargita, Tóth Gábor K., Vágvölgyi Csaba, Marx Florentine, Galgóczy László
Dátum:2018
ISSN:1664-302X
Megjegyzések:The increasing number of life-threatening Candida infections caused by antifungal drug-resistant strains urges the development of new therapeutic strategies. The small, cysteine-rich, and cationic Neosartorya fischeri antifungal protein 2 (NFAP2) effectively inhibits the growth of Candida spp. Limiting factors of its future application, are the low-yield production by the native producer, unavailable information about potential clinical application, and the unsolved relationship between the structure and function. In the present study we adopted a Penicillium chrysogenum-based expression system for bulk production of recombinant NFAP2. Furthermore, solid-phase peptide synthesis and native chemical ligation were applied to produce synthetic NFAP2. The average yield of recombinant and synthetic NFAP2 was 40- and 16-times higher than in the native producer, respectively. Both proteins were correctly processed, folded, and proved to be heat-stable. They showed the same minimal inhibitory concentrations as the native NFAP2 against clinically relevant Candida spp. Minimal inhibitory concentrations were higher in RPMI 1640 mimicking the human inner fluid than in a low ionic strength medium. The recombinant NFAP2 interacted synergistically with fluconazole, the first-line Candida therapeutic agent and significantly decreased its effective in vitro concentrations in RPMI 1640. Functional mapping with synthetic peptide fragments of NFAP2 revealed that not the evolutionary conserved antimicrobial ?-core motif, but the mid-N-terminal part of the protein influences the antifungal activity that does not depend on the primary structure of this region. Preliminary nucleic magnetic resonance measurements signed that the produced recombinant NFAP2 is suitable for further structural investigations.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Neosartorya fischeri antifungal protein 2
recombinant protein
protein synthesis
anti-candidal activity
protein structure
functional mapping
Megjelenés:Frontiers in Microbiology. - 9 : 393 (2018), p. 1-12. -
További szerzők:Váradi Györgyi Borics Attila Batta Gyula (1953-) (molekula-szerkezet kutató) Kele Zoltán Vendrinszky Ákos Tóth Roberta Ficze Hargita Tóth Gábor K. Vágvölgyi Csaba Marx, Florentine Galgóczy László (1950-)
Pályázati támogatás:PD 120808, ANN 122833, ANN 110821
OTKA
GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.2-15-2016-00014
GINOP
GINOP-2.3.2-15-2016-00035
GINOP
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3.

001-es BibID:BIBFORM113291
035-os BibID:(cikkazonosító)e4692 (Scopus)85162082479 (WoS)001010056600001
Első szerző:Váradi Györgyi
Cím:Hard nut to crack: Solving the disulfide linkage pattern oftheNeosartorya(Aspergillus)fischeriantifungal protein 2 / Györgyi Váradi Zoltán Kele András Czajlik, Attila Borics, Gábor Bende, Csaba Papp, Gábor Rákhely,Gábor K. Tóth, Gyula Batta, László Galgóczy
Dátum:2023
ISSN:0961-8368
Megjegyzések:As a consequence of the fast resistance spreading, a limited number of drugs are available to treat fungal infections. Therefore, there is an urgent need to develop new antifungal treatment strategies. The features of a disulfide bond- stabilized antifungal protein, NFAP2 secreted by the mold Neosartorya (Asper- gillus) fischeri render it to be a promising template for future protein-based antifungal drug design, which requires knowledge about the native disulfide linkage pattern as it is one of the prerequisites for biological activity. However, in the lack of tryptic and chymotryptic proteolytic sites in the ACNCPNNCK sequence, the determination of the disulfide linkage pattern of NFAP2 is not easy with traditional mass spectrometry-based methods. According to in silico predictions working with a preliminary nuclear magnetic resonance (NMR) solution structure, two disulfide isomers of NFAP2 (abbacc and abbcac) were possible. Both were chemically synthesized; and comparative reversed-phase high-performance liquid chromatography, electronic circular dichroism and NMR spectroscopy analyses, and antifungal susceptibility and efficacy tests indicated that the abbcac is the native pattern. This knowledge allowed rational modification of NAFP2 to improve the antifungal efficacy and spectrum through the modulation of the evolutionarily conserved ?-core region, which is responsible for the activity of several antimicrobial peptides. Disruption of the steric structure of NFAP2 upon ?-core modification led to the conclusions that this motif may affect the formation of the biologically active three-dimensional structure, and that the ?-core modulation is not an efficient tool to improve the antifungal efficacy or to change the antifungal spectrum of NFAP2.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Protein Science. - 32 : 7 (2023), p. 1-13. -
További szerzők:Kele Zoltán Czajlik András (1975-) (gyógyszerész) Borics Attila Bende Gábor Papp Csaba Rákhely Gábor Tóth Gábor K. Batta Gyula (1953-) (molekula-szerkezet kutató) Galgóczy László (1950-)
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4.

001-es BibID:BIBFORM109184
035-os BibID:(Scopus)85149121543 (WoS)000939526000001
Első szerző:Váradi Györgyi
Cím:Confirmation of the Disulfide Connectivity and Strategies for Chemical Synthesis of the Four-Disulfide-Bond-Stabilized Aspergillus giganteus Antifungal Protein, AFP / Györgyi Váradi, Gyula Batta, László Galgóczy, Dorottya Hajdu, Ádám Fizil, András Czajlik, Máté Virágh, Zoltán Kele, Vera Meyer, Sascha Jung, Florentine Marx, Gábor K. Tóth
Dátum:2023
ISSN:0163-3864 1520-6025
Megjegyzések:Emerging fungal infections require new, more efficient antifungal agents and therapies. AFP, a protein from Aspergillus giganteus with four disulfide bonds, is a promising candidate because it selectively inhibits the growth of filamentous fungi. In this work, the reduced form of AFP was prepared using native chemical ligation. The native protein was synthesized via oxidative folding with uniform protection for cysteine thiols. AFP's biological activity depends heavily on the pattern of natural disulfide bonds. Enzymatic digestion and MS analysis provide proof for interlocking disulfide topology (abcdabcd) that was previously assumed. With this knowledge, a semi-orthogonal thiol protection method was designed. By following this strategy, out of a possible 105, only 6 disulfide isomers formed and 1 of them proved to be identical with the native protein. This approach allows the synthesis of analogs for examining structure-activity relationships and, thus, preparing AFP variants with higher antifungal activity.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Journal of Natural Products. - 86 : 4 (2023), p. 782-790. -
További szerzők:Batta Gyula (1953-) (molekula-szerkezet kutató) Galgóczy László (1950-) Hajdu Dorottya (1987-) (biológus) Fizil Ádám (1988-) (biológus) Czajlik András (1975-) (gyógyszerész) Virágh Máté Kele Zoltán Meyer, Vera Jung, Sascha Marx, Florentine Tóth Gábor K.
Pályázati támogatás:NKFIH TKP2021-EGA-32
Egyéb
NKFIH FK 134343
Egyéb
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Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM078607
035-os BibID:(cikkazonosító)5 (WoS)000457124000003 (Scopus)85061664892
Első szerző:Váradi Györgyi
Cím:Structure and synthesis of antifungal disulfide β-strand proteins from filamentous fungi / Györgyi Váradi, Gábor K. Tóth, Gyula Batta
Dátum:2018
ISSN:2076-2607
Megjegyzések:The discovery and understanding of the mode of action of new antimicrobial agents is extremely urgent, since fungal infections cause 1.5 million deaths annually. Antifungal peptides and proteins represent a significant group of compounds that are able to kill pathogenic fungi. Based on phylogenetic analyses the ascomycetous, cysteine-rich antifungal proteins can be divided into three different groups: Penicillium chrysogenum antifungal protein (PAF), Neosartorya fischeri antifungal protein 2 (NFAP2) and ?bubble-proteins" (BP) produced, for example, by P. brevicompactum. They all dominantly have β-strand secondary structures that are stabilized by several disulfide bonds. The PAF group (AFP antifungal protein from Aspergillus giganteus, PAF and PAFB from P. chrysogenum, Neosartorya fischeri antifungal protein (NFAP)) is the best characterized with their common β-barrel tertiary structure. These proteins and variants can efficiently be obtained either from fungi production or by recombinant expression. However, chemical synthesis may be a complementary aid for preparing unusual modifications, e.g., the incorporation of non-coded amino acids, fluorophores, or even unnatural disulfide bonds. Synthetic variants up to ca. 6-7 kDa can also be put to good use for corroborating structure determination. A short overview of the structural peculiarities of antifungal β-strand disulfide bridged proteins will be given. Here, we describe the structural propensities of some known antifungal proteins from filamentous fungi which can also be prepared with modern synthetic chemistry methods.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
structure
antifungal protein
chemical synthesis
solid-phase peptide synthesis
native chemical ligation
disulfide bond
NFAP2
PAF
Megjelenés:Microorganisms. - 7 : 1 (2018), p. 1-10. -
További szerzők:Tóth Gábor (Szeged) Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.2-15-2016-00014
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
Internet cím:DOI
Intézményi repozitóriumban (DEA) tárolt változat
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6.

001-es BibID:BIBFORM057855
Első szerző:Váradi Györgyi
Cím:Több diszulfidhíd kötést tartalmazó peptidek szintézise / Váradi Györgyi, Rákosi Kinga, Kele Zoltán, Batta Gyula, Tóth K. Gábor
Dátum:2014
ISSN:1418-9933
Tárgyszavak:Természettudományok Kémiai tudományok magyar nyelvű folyóiratközlemény hazai lapban
Megjelenés:Magyar Kémiai Folyóirat. - 120 : 2-3 (2014), p. 122-126. -
További szerzők:Rákosi Kinga Kele Zoltán Batta Gyula (1953-) (molekula-szerkezet kutató) Tóth K. Gábor
Pályázati támogatás:TÁMOP-4.2.2.A-11/1/KONV-2012-0047
TÁMOP
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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7.

001-es BibID:BIBFORM056390
Első szerző:Váradi Györgyi
Cím:Synthesis of PAF, an Antifungal Protein from P. chrysogenum, by Native Chemical Ligation : Native Disulfide Pattern and Fold Obtained upon Oxidative Refolding / Györgyi Váradi, Gábor K. Tóth, Zoltán Kele, László Galgóczy, Ádám Fizil, Gyula Batta
Dátum:2013
ISSN:0947-6539
Megjegyzések:The folding of disulfide proteins is of considerable interest because knowledge of this may influence our present understanding of protein folding. However, sometimes even the disulfide pattern cannot be unequivocally determined by the available experimental techniques. For example, the structures of a few small antifungal proteins (PAF, AFP) have been disclosed recently using NMR spectroscopy but with some ambiguity in the actual disulfide pattern. For this reason, we carried out the chemical synthesis of PAF. Probing different approaches, the oxidative folding of the synthetic linear PAF yielded a folded protein that has identical structure and antifungal activity as the native PAF. In contrast, unfolded linear PAF was inactive, a result that may have implications concerning its redox state in the mode of action.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
antifungal agents
NMR spectroscopy
peptides
protein folding
solid-phase synthesis
Molekulatudomány
Megjelenés:Chemistry-A European Journal 19 : 38 (2013), p. 12684-12692. -
További szerzők:Tóth Gábor K. Kele Zoltán Galgóczy László (1950-) Fizil Ádám (1988-) (biológus) Batta Gyula (1953-) (molekula-szerkezet kutató)
Pályázati támogatás:TÁMOP-4.2.1/B-09/1/KONV-2010-0005
TÁMOP
TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
Szerkezeti biológia és molekuláris felismerés
TÁMOP-4.2.2.A-11/1/KONV-2012-0035
TÁMOP
CK 77515, K 105459, PD83355
OTKA
OMAA 83öu7 - Austrian-Hungarian Action
Egyéb
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8.

001-es BibID:BIBFORM086163
035-os BibID:(cikkazonosító)183246
Cím:Two small, cysteine-rich and cationic antifungal proteins from Penicillium chrysogenum : a comparative study of PAF and PAFB / A. Huber, L. Galgóczy, G. Váradi, J. Holzknecht, A. Kakar, N. Malanovic, R. Leber, J. Koch, M. A. Keller, G. Batta, G. K. Tóth, F. Marx
Dátum:2020
ISSN:0005-2736
Megjegyzések:The filamentous fungus Penicillium chrysogenum Q176 secretes the antimicrobial proteins (AMPs) PAF and PAFB, which share a compact disulfide-bond mediated, beta-fold structure rendering them highly stable. These two AMPs effectively inhibit the growth of human pathogenic fungi in micromolar concentrations and exhibit antiviral potential without causing cytotoxic effects on mammalian cells in vitro and in vivo. The antifungal mechanism of action of both AMPs is closely linked to - but not solely dependent on - the lipid composition of the fungal cell membrane and requires a strictly regulated protein uptake into the cell, indicating that PAF and PAFB are not canonical membrane active proteins. Variations in their antifungal spectrum and their killing dynamics point towards a divergent mode of action related to their physicochemical properties and surface charge distribution. In this review, we relate characteristic features of PAF and PAFB to the current knowledge about other AMPs of different sources. In addition, we present original data that have never been published before to substantiate our assumptions and provide evidences that help to explain and understand better the mechanistic function of PAF and PAFB. Finally, we underline the promising potential of PAF and PAFB as future antifungal therapeutics.
Tárgyszavak:Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Antimicrobial proteins and peptides
Penicillium chrysogenum
beta-Fold structure
gamma-Core
Fungal membrane lipids
Endocytosis
Apoptosis
Megjelenés:Biochimica et Biophysica Acta (BBA). Biomembranes. - 1862 : 8 (2020), p. 1-14. -
További szerzők:Huber Anna Galgóczy László (1950-) Váradi Györgyi Holzknecht, Jeanett Kakar, A. Malanovic, N. Leber, R. Koch, J. Keller, M. A. Batta Gyula (1953-) (molekula-szerkezet kutató) Tóth Gábor K. Marx, Florentine
Pályázati támogatás:GINOP-2.3.2-15-2016-00008
GINOP
GINOP-2.3.3-15-2016-00004
GINOP
GINOP-2.3.2-15-2016-00014
GINOP
NKFI 20391-3/2018/FEKUSTRAT
Egyéb
TUDFO/47138-1/2019-ITM FIKP
Egyéb
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