Váradi, Györgyi and Batta, Gyula and Galgóczi, László Norbert and Hajdu, Dorottya Zsuzsanna and Fizil, Ádám and Czajlik, András and Virágh, Máté and Kele, Zoltán and Tóth, Gábor (2023) Confirmation of the Disulfide Connectivity and Strategies for Chemical Synthesis of the Four-Disulfide-Bond-Stabilized Aspergillus giganteus Antifungal Protein, AFP. JOURNAL OF NATURAL PRODUCTS, 86 (4). pp. 782-790. ISSN 0163-3864
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Abstract
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.
Item Type: | Article |
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Additional Information: | Funding Agency and Grant Number: Hungarian National Research, Development [TKP2021-EGA-32]; Innovation Office-NKFIH; Hungarian National Research, Development and Innovation Office-NKFIH [FK 134343]; Austrian Science Fund [392923329]; Deutsche Forschungsgemeinschaft (DFG); [I1644-B20] Funding text: We thank D. Bratschun-Khan for her technical assistance. G.V. and G.K.T. were supported by the TKP2021-EGA-32 fund of the Hungarian National Research, Development, and Innovation Office-NKFIH, and L.G. was financed by the Hungarian National Research, Development and Innovation Office-NKFIH, FK 134343 project. This work was financed by the Austrian Science Fund (FWF I1644-B20) to F.M. and by the Deutsche Forschungsgemeinschaft (DFG, GRK2473 Bioactive Peptides project number 392923329) to S.J. and V.M. |
Subjects: | Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia Q Science / természettudomány > QR Microbiology / mikrobiológia |
SWORD Depositor: | MTMT SWORD |
Depositing User: | MTMT SWORD |
Date Deposited: | 26 Sep 2023 13:23 |
Last Modified: | 26 Sep 2023 13:23 |
URI: | http://real.mtak.hu/id/eprint/175138 |
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