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Publikationen - Natur- und Wirkstoffchemie

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Publikation

Vasco, A. V.; Méndez, Y.; González, C.; Pérez, C. S.; Reguera, L.; Wessjohann, L. A.; Rivera, D. G.; Advancing multicomponent strategies to macrobicyclic peptides ChemBioChem 24, e202300229, (2023) DOI: 10.1002/cbic.202300229

Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected β-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.
Publikation

Uddin, N.; Muhammad, N.; Ali, S. S.; Ullah, R.; Bari, A.; Hussain, H.; Zhu, D.; Characterization of the genetic variability within Ziziphus nummularia genotypes by phenotypic traits and SSR markers with special reference to geographic distribution Genes 14, 155, (2023) DOI: 10.3390/genes14010155

Understanding the impacts and constraints of climate change on Ziziphus nummularia′s geographical distribution is crucial for its future sustainability. In this study, we analyze information obtained from the field investigation, the distribution and response of climatic changes of Ziziphus nummularia by the use of ArcGIS analysis. The genetic diversity of 180 genotypes from three populations was studied by morphological attributes and simple sequence repeat (SSR). The results showed that the significant bioclimatic variable limiting the distribution of Z. nummularia was the mean temperature (bio 10_18.tif and bio19). Under the current climatic change, the suitable growth region of Z. nummularia is Swat (35.22° N, 72.42° E), while the future distribution would be Buner (34.39° N, 72.61° E), respectively. A total of 11 phenotypic traits were noted and had significant phenotypic variation among the traits. A total of 120 alleles were amplified. The alleles per locus ranged from 2 to 6, averaging 4.42, whereas PIC ranged from 0.33 to 0.79. Within a mean value of 0.67 per locus, expected heterozygosity was 0.57, observed heterozygosity was 0.661, and average gene diversity was 0.49. Flow estimates (6.41) indicated frequent gene flow within genotypes. The clustering, STRUCTURE, and PCoA analysis indicated Swat and Buner migration routes and evolution as well. The results indicated the prevalence of genetic variability and relationships among Z. nummularia across geographical boundaries had retained unique alleles. This may facilitate the development of agronomically desirable cultivars. However, climate change has impacted species distributions, requiring strategies to conserve genetic resources in different areas.
Publikation

Sun, X.; Xu, L.; Yan, H.; Li, P.; Hussain, H.; Liu, J.; Zhang, J.; Wang, D.; Isolation and purification of high polar glycosides from aerial parts of Gynostemma pentaphyllum (Thunb.) Makino by linear gradient counter‐current chromatography coupled with inner‐recycling mode J Sep Sci 46, 2300238, (2023) DOI: 10.1002/jssc.202300238

Gynostemma pentaphyllum (Thunb.) Makino represents the popular health food and supplemental product with broad pharmacological activities. The highly polar glycosides, including flavonoids and saponins, are major effective active components that contain diverse sugar positions and quantities, which result in diverse chemical polarities, making it challenging to separate and isolate these components. The present work described the rapid and efficient linear gradient counter‐current chromatography to preparatively separate glycosides from aboveground parts of G. pentaphyllum. Besides, the ethyl acetate and n‐butanol binary mobile phases were achieved through adjusting associated proportions. Six glycosides, including quercetin‐3‐O‐neohesperidoside (1), kaempferol‐3‐O‐robinobioside (2), kaempferol‐3‐O‐neohesperidoside (3), gypenoside LVI (4), ginsenoside Rb3 (5), and gypenoside XLVI (6), were isolated at the purities greater than 98%. Moreover, electrospray ionization mass spectrometry and nuclear magnetic resonance tandem mass spectrometry were conducted for structural identification. According to our findings, the established linear gradient counter‐current chromatography was an efficient approach to separate the highly polar glycosides from aboveground parts of G. pentaphyllum. Our proposed strategy can be used to separate active compounds from other complex natural products.
Publikation

Meng, S.; Li, Z.; Ji, Y.; Ruff, A. J.; Liu, L.; Davari, M. D.; Schwaneberg, U.; Introduction of aromatic amino acids in electron transfer pathways yielded improved catalytic performance of cytochrome P450s Chin. J. Catal. 49, 81-90, (2023) DOI: 10.1016/s1872-2067(23)64445-6

Cytochrome P450s are versatile catalysts for biosynthesis applications. In the P450 catalytic cycle, two electrons are required to reduce the heme iron and activate the subsequent reductions through proposed electron transfer pathways (eTPs), which often represent the rate-limiting step in reactions. Herein, the P450 BM3 from Bacillus megaterium was engineered for improved catalytic performance by redesigning proposed eTPs. By introducing aromatic amino acids on eTPs of P450 BM3, the “best” variant P2H02 (A399Y/Q403F) showed 13.9-fold improved catalytic efficiency (kcat/KM = 913.5 L mol−1 s−1) compared with P450 BM3 WT (kcat/KM = 65.8 L mol−1 s−1). Molecular dynamics simulations and electron hopping pathways analysis revealed that aromatic amino acid substitutions bridging the cofactor flavin mononucleotide and heme iron could increase electron transfer rates and improve catalytic performance. Moreover, the introduction of tyrosines showed positive effects on catalytic efficiency by potentially protecting P450 from oxidative damage. In essence, engineering of eTPs by aromatic amino acid substitutions represents a powerful approach to design catalytically efficient P450s (such as CYP116B3) and could be expanded to other oxidoreductases relying on long-range electron transfer pathways.
Publikation

Liu, Y.; Li, Z.; Cao, C.; Zhang, X.; Meng, S.; Davari, M. D.; Xu, H.; Ji, Y.; Schwaneberg, U.; Liu, L.; Engineering of substrate tunnel of P450 CYP116B3 though machine learning Catalysts 13, 1228, (2023) DOI: 10.3390/catal13081228

The combinatorial complexity of the protein sequence space presents a significant challenge for recombination experiments targeting beneficial positions. To overcome these difficulties, a machine learning (ML) approach was employed, which was trained on a limited literature dataset and combined with iterative generation and experimental data implementation. The PyPEF method was utilized to identify existing variants and predict recombinant variants targeting the substrate channel of P450 CYP116B3. Through molecular dynamics simulations, eight multiple-substituted improved variants were successfully validated. Specifically, the RMSF of variant A86T/T91H/M108S/A109M/T111P was decreased from 3.06 Å (wild type) to 1.07 Å. Additionally, the average RMSF of the variant A86T/T91P/M108V/A109M/T111P decreased to 1.41 Å, compared to the wild type’s 1.53 Å. Of particular significance was the prediction that the variant A86T/T91H/M108G/A109M/T111P exhibited an activity approximately 15 times higher than that of the wild type. Furthermore, during the selection of the regression model, PLS and MLP regressions were compared. The effect of data size and data relevance on the two regression approaches has been summarized. The aforementioned conclusions provide evidence for the feasibility of the strategy that combines ML with experimental approaches. This integrated strategy proves effective in exploring potential variations within the protein sequence space. Furthermore, this method facilitates a deeper understanding of the substrate channel in P450 CYP116B3.
Publikation

Lam, Y. T. H.; Hoppe, J.; Dang, Q. N.; Porzel, A.; Soboleva, A.; Brandt, W.; Rennert, R.; Hussain, H.; Davari, M. D.; Wessjohann, L.; Arnold, N.; Purpurascenines A–C, azepino-indole alkaloids from Cortinarius purpurascens: Isolation, biosynthesis, and activity studies on the 5-HT2A receptor J. Nat. Prod. 86, 1373-1384, (2023) DOI: 10.1021/acs.jnatprod.2c00716

Three previously undescribed azepino-indole alkaloids, named purpurascenines A−C (1−3), together with the new-to-nature 7-hydroxytryptophan (4) as well as two known compounds, adenosine (5) and riboflavin (6), were isolated from fruiting bodies of Cortinarius purpurascens Fr. (Cortinariaceae). The structures of 1−3 were elucidated based on spectroscopic analyses and ECD calculations. Furthermore, the biosynthesis of purpurascenine A (1) was investigated by in vivo experiments using 13C-labeled sodium pyruvate, alanine, and sodium acetate incubated with fruiting bodies of C. purpurascens. The incorporation of 13C into 1 was analyzed using 1D NMR and HRESIMS methods. With [3-13C]-pyruvate, a dramatic enrichment of 13C was observed, and hence a biosynthetic route via a direct Pictet−Spengler reaction between α-keto acids and 7-hydroxytryptophan (4) is suggested for the biosynthesis of purpurascenines A−C (1−3). Compound 1 exhibits no antiproliferative or cytotoxic effects against human prostate (PC-3), colorectal (HCT-116), and breast (MCF-7) cancer cells. An in silico docking study confirmed the hypothesis that purpurascenine A (1) could bind to the 5-HT2A serotonin receptor’s active site. A new functional 5-HT2A receptor activation assay showed no functional agonistic but some antagonistic effects of 1 against the 5-HT-dependent 5-HT2A activation and likely antagonistic effects on putative constitutive activity of the 5-HT2A receptor.
Publikation

Kappen, J.; Manurung, J.; Fuchs, T.; Vemulapalli, S. P. B.; Schmitz, L. M.; Frolov, A.; Agusta, A.; Muellner-Riehl, A. N.; Griesinger, C.; Franke, K.; Wessjohann, L. A.; Challenging structure elucidation of lumnitzeralactone, an ellagic acid derivative from the Mangrove Lumnitzera racemosa Mar. Drugs 21, 242, (2023) DOI: 10.3390/md21040242

The previously undescribed natural product lumnitzeralactone (1), which represents a derivative of ellagic acid, was isolated from the anti-bacterial extract of the Indonesian mangrove species Lumnitzera racemosa Willd. The structure of lumnitzeralactone (1), a proton-deficient and highly challenging condensed aromatic ring system, was unambiguously elucidated by extensive spectroscopic analyses involving high-resolution mass spectrometry (HRMS), 1D 1H and 13C nuclear magnetic resonance spectroscopy (NMR), and 2D NMR (including 1,1-ADEQUATE and 1,n-ADEQUATE). Determination of the structure was supported by computer-assisted structure elucidation (CASE system applying ACD-SE), density functional theory (DFT) calculations, and a two-step chemical synthesis. Possible biosynthetic pathways involving mangrove-associated fungi have been suggested.
Publikation

Jalil, K.; Ahmad, S.; Islam, N.; Ullah, R.; Jalil, Q.; Sulaiman, S.; Sajjad, A.; Ullah, R.; Alqahtani, A. S.; Bari, A.; Hussain, H.; Ali, E. A.; One pot synthesis, biological efficacy of AuNPs and Au-Amoxicillin conjugates functionalized with crude flavonoids extract of Micromeria biflora Molecules 28, 3320, (2023) DOI: 10.3390/molecules28083320

Amoxicillin is the most widely used antibiotic in human medicine for treating bacterial infections. However, in the present research, Micromeria biflora’s flavonoids extract mediated gold nanoparticles (AuNPs) were conjugated with amoxicillin (Au-amoxi) to study their efficacy against the inflammation and pain caused by bacterial infections. The formation of AuNPs and Au-amoxi conjugates were confirmed by UV–visible surface plasmon peaks at 535 nm and 545 nm, respectively. The scanning electron microscopy (SEM), zeta potential (ZP), and X-ray diffraction (XRD) studies reveal that the size of AuNPs and Au-amoxi are found to be 42 nm and 45 nm, respectively. Fourier-transform infrared spectroscopy (FT-IR) absorption bands at 3200 cm−1, 1000 cm−1, 1500 cm−1, and 1650 cm−1 reveal the possible involvement of different moieties for the formation of AuNPs and Au-amoxi. The pH studies show that AuNPs and Au-amoxi conjugates are stable at lower pH. The carrageenan-induced paw edema test, writhing test, and hot plate test were used to conduct in vivo anti-inflammatory and antinociceptive studies, respectively. According to in vivo anti-inflammatory activity, Au-amoxi compounds have higher efficiency (70%) after 3 h at a dose of 10 mg/kg body weight as compared to standard diclofenac (60%) at 20 mg/kg, amoxicillin (30%) at 100 mg/kg, and flavonoids extract (35%) at 100 mg/kg. Similarly, for antinociceptive activities, writhing test results show that Au-amoxi conjugates produced the same number of writhes (15) but at a lower dose (10 mg/kg) compared to standard diclofenac (20 mg/kg). The hot plate test results demonstrate that the Au-amoxi has a better latency time of 25 s at 10 mg/kg dose when compared to standard Tramadol of 22 s at 30 mg/ kg, amoxicillin of 14 s at 100 mg/kg, and extract of 14 s at 100 mg/kg after placing the mice on the hot plate for 30, 60, and 90 min with a significance of (p ≤ 0.001). These findings show that the conjugation of AuNPs with amoxicillin to form Au-amoxi can boost its anti-inflammatory and antinociceptive potential caused by bacterial infections.
Publikation

Ihlenburg, R. B. J.; Petracek, D.; Schrank, P.; Davari, M. D.; Taubert, A.; Rothenstein, D.; Identification of the first sulfobetaine hydrogel‐binding peptides via phage display assay Macromolecular Rapid Communications 44, 2200896, (2023) DOI: 10.1002/marc.202200896

Using the M13 phage display, a series of 7- and 12-mer peptides which interact with new sulfobetaine hydrogels are identified. Two peptides each from the 7- and 12-mer peptide libraries bind to the new sulfobetaine hydrogels with high affinity compared to the wild-type phage lacking a dedicated hydrogel binding peptide. This is the first report of peptides binding to zwitterionic sulfobetaine hydrogels and the study therefore opens up the pathway toward new phage or peptide/hydrogel hybrids with high application potential.
Publikation

Hussain, H.; Xiao, J.; Ali, A.; Green, I. R.; Westermann, B.; Unusually cyclized triterpenoids: occurrence, biosynthesis and chemical synthesis Nat. Prod. Rep. 40, 412-451, (2023) DOI: 10.1039/d2np00033d

Covering: 2009 to 2021Biosynthetically, most of the syntheses of triterpenes follow the cascade cyclization and rearrangement of the acyclic precursors viz., squalene (S) and 2,3-oxidosqualene (OS), which lead to the very well known tetra- and pentacyclic triterpene skeletons. Aside from these, numerous other triterpenoid molecules are also reported from various natural sources and their structures are derived from \"S\" and \"OS\" via some unusual cyclization operations which are different from the usual tetra- and pentacyclic frameworks. Numerous compelling advances have been made and reported in the identification of these unusual cyclized mono-, di-, tri- and tetracyclic triterpenes between 2009 and 2021. Besides a dramatic increase in the newly isolated uncommon cyclized triterpenoids, substantial progress in the (bio)-synthesis of these triterpenes has been published along with significant progress in their biological effects. In this review, 180 new unusual cyclized triterpenoids together with their demonstrated biogenetic pathways, syntheses and biological effects will be categorized and discussed.
  • Die Leibniz-Gemeinschaft
  • Digitalisierung in der Landwirtschaft
  • Martin-Luther Universität Halle
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