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Department of Bioorganic Chemistry is one of 14 departments of Faculty of Chemistry, Wrocław University of Science and Technology. It is headed by Łukasz Berlicki and formed by 5 research groups of: prof. Paweł Kafarski, prof. Artur Mucha, prof. Łukasz Berlicki, Dr. Rafał Kowalczyk and Dr. Rafał Latajka. The main research areas are on a border of chemistry and biology.





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[EN] One of the Berlicki Lab's main scientific interests is the application of peptide foldamers as building blocks in...

Opublikowany przez Berlicki Lab Poniedziałek, 17 sierpnia 2020

Recent papers

Monosubstituted Acetophenone Thiosemicarbazones as Potent Inhibitors of Tyrosinase: Synthesis, Inhibitory Studies, and Molecular Docking.
Hałdys, K.; Goldeman, W.; Anger-Góra, N.; Rossowska, J.; Latajka, R.
Pharmaceuticals 2021, 14, 74
DOI: 10.3390/ph14010074

A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC50) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries.

Recent papers

Hierarchical approach for the rational construction of helix-containing nanofibrils using α,β-peptides.
Szefczyk, M.; Szulc, N.; Gąsior-Głogowska, M.; Modrak-Wójcik, A.; Bzowska, A.; Majstrzyk, W.; Taube, M.; Kozak, M.; Gotszalk, T.; Rudzińska-Szostak, E.; Berlicki, Ł.
Nanoscale 2021, accepted.
DOI: 10.1039/D0NR04313C

The rational design of novel self-assembled nanomaterials based on peptides remains a great challenge in modern chemistry. A hierarchical approach for the construction of nanofibrils based on α,β-peptide foldamers is proposed. The incorporation of a helix-promoting trans-(1S,2S)-2-aminocyclopentanecarboxylic acid residue in the outer positions of the model coiled-coil peptide led to its increased conformational stability, which was established consistently by the results of CD, NMR and FT-IR spectroscopy. The designed oligomerization state in the solution of the studied peptides was confirmed using analytical ultracentrifugation. Moreover, the cyclopentane side chain allowed additional interactions between coiled-coil-like structures to direct the self-assembly process towards the formation of well-defined nanofibrils, as observed using AFM and TEM techniques.

Recent papers

Covalent Inhibition of Bacterial Urease by Bifunctional Catechol-Based Phosphonates and Phosphinates
Pagoni, A.; Grabowiecka, A.; Tabor, W.; Mucha, A.; Vassiliou, S.; Berlicki, Ł.
J. Med. Chem. 2021, 64, 404
DOI: 10.1021/acs.jmedchem.0c01143

In this study, a new class of bifunctional inhibitors of bacterial ureases, important molecular targets for antimicrobial therapies, was developed. The structures of the inhibitors consist of a combination of a phosphonate or (2-carboxyethyl)phosphinate functionality with a catechol-based fragment, which are designed for complexation of the catalytic nickel ions and covalent bonding with the thiol group of Cys322, respectively. Compounds with three types of frameworks, including β-3,4-dihydroxyphenyl-, α-3,4-dihydroxybenzyl-, and α-3,4-dihydroxybenzylidene-substituted derivatives, exhibited complex and varying structure-dependent kinetics of inhibition. Among irreversible binders, methyl β-(3,4-dihydroxyphenyl)-β-(2-carboxyethyl)phosphorylpropionate was observed to be a remarkably reactive inhibitor of Sporosarcina pasteurii urease (kinact/KI = 10 420 s-1 M-1). The high potential of this group of compounds was also confirmed in Proteus mirabilis whole-cell-based inhibition assays. Some compounds followed slow-binding and reversible kinetics, e.g., methyl β-(3,4-dihydroxyphenyl)-β-phosphonopropionate, with Ki* = 0.13 μM, and an atypical low dissociation rate (residence time τ = 205 min).

Recent papers

Novel, automated, semi-industrial modular photobioreactor system for cultivation of demanding microalgae that produce fine chemicals—The next story of H. pluvialis and astaxanthin
Borowiak, D.; Lenartowicz, P.; Grzebyk, M.; Wisniewski, M.; Lipok, J.; Kafarski, P.
Algal Res. 2021, 53, 1
DOI: 10.1016/j.algal.2020.102151

Recently, there has been increased interest in the use of microorganisms in the production of pharmaceuticals, nutraceuticals and energy supply products, which is due to their rapid growth rate and ability to biosynthesize fine chemicals or biotransform specific xenobiotics. To achieve the desired scale of production and optimization of microbial cultures, it is necessary to design bioreactors that enable process automation, control of working parameters, reduction of microbial and chemical contaminations, and culture independence of climate conditions. In response to this need, an original, modular airlift-type photobioreactor system was designed and manufactured. This novel semitechnical system, with a total volume of 1000 dm3, was operated via computer control, which enabled the creation of time profiles of red, blue and white LED illumination and of carbon dioxide and air dosing. The quality and usefulness of the developed system was demonstrated via the case study, namely two-stage cultivation of the microalgae Haematococcus pluvialis — a species commonly used in the production of natural astaxanthin. The experimentally developed procedure ensures a repeatable and efficient biomass multiplication process and the maintenance of a light- and chemical-mediated effective stress mechanismthat allows the production of up to 3.2% natural astaxanthin in terms of dry biomass.

Recent papers

Stereoselectivity Enhancement During the Generation of Three Contiguous Stereocenters in Tetrahydrothiophenes
Mała, Ż. A.; Janicki, M. J.; Niedźwiecka, N. H.; Góra, R. W.; Konieczny, K. A.; Kowalczyk, R.
ChemCatChem 2020, accepted.
DOI: 10.1002/cctc.202001583

Application of carefully designed Cinchona alkaloid based squaramides resulted in the formation of three contiguous stereocenters in enantio‐ and diastereoselective Sulfa‐Michael/intramolecular aldol reactions cascade. Increase of the temperature to 333 K in reaction of mercaptoacetic aldehyde and various en‐ynones allowed the rise of the reaction rate while not affecting the enantioselectivity nor diastereoselectivity. Stereoselectivity was dependent on the structure of the hydrogen‐bonding unit, thus revealing the importance of weak interactions in the formation of the multifunctional tetrahydrothiophenes. Kohn‐Sham Density Functional Theory results suggest that a perfect fit of the electrophile and squaramide via tailored (+)N−H hydrogen bonding and π–π stacking interactions were the main factors of the chirality transfer.

Recent papers

Cinchona squaramide-catalyzed intermolecular desymmetrization of 1,3-diketones leading to chiral 1,4-dihydropyridines.
Dajek, M.; Pruszczyńska, A.; Konieczny, K. A.; Kowalczyk, R.
Adv. Synth. Catal. 2020, 362, 3613
DOI: 10.1002/adsc.202000455

Addition of prochiral cyclic 1,3‐diketones to Michael acceptors applying bifunctional Cinchona‐derived squaramides resulted in chiral adducts with stereoselectivities of up to 99% ee and allowed for desymmetrization of the nucleophile. These labile hemiacetal intermediates were transformed to new 1,4‐dihydropyridines with high diastereoselectivities and no erosion of optical purity. Their further oxidation to pyridine followed by Fisher indolization provided chiral pyridine‐indoles.

Recent papers

Access to α-Aminophosphonic Acid Derivatives and Phosphonopeptides by [Rh(P–OP)]-Catalyzed Stereoselective Hydrogenation
Fernández-Pérez, H.; Lenartowicz, P.; Carreras, L.; Grabulosa, A.; Kafarski, P. Vidal-Ferran, A.
J. Org. Chem. 2020, 85, 14779
DOI: 10.1021/acs.joc.0c00914

The hydrogenation of N-substituted vinylphosphonates using rhodium complexes derived from P–OP ligands L1, ent-L1, or (R,R)-Me-DuPHOS as catalysts has been successfully accomplished, achieving very high levels of stereoselectivity (up to 99% ee or de). The described synthetic strategy allowed for the efficient preparation of α-aminophosphonic acid derivatives and phosphonopeptides, which are valuable building blocks for the preparation of biologically relevant molecules.

Recent papers

Cosmeceutical Peptides in the Framework of Sustainable Wellness Economy
Errante F.; Ledwoń P.; Latajka R.; Rovero P.; Papini A.M.
Frontiers in Chemistry 2020, 8, 572923
DOI: 10.3389/fchem.2020.572923

Among the many aspects that contribute to the wellness of each individual, healthy and younger-looking skin play a relevant role, as clearly shown by the important growth of the skin-care products market observed in recent years. In this scenario, the field of cosmeceuticals appears particularly promising, being based on cosmetic products containing active ingredients. Among these, several peptides were proposed for cosmeceutical applications, thanks to their specific interaction with biological targets. In thismini-review, we report some of themost investigated and used peptides for cosmetic formulations, taking into account that cosmeceutical peptides are basically divided into three main categories (i.e., neurotransmitter inhibitors, carriers, and signal peptides). Special attention was payed to the scientific studies supporting the claimed biological activity of these peptides, as a fundamental aspect that should underpin the growth of this field in the framework of a sustainable wellness economy.

Recent papers

N-Benzyl Residues as the P1' Substituents in Phosphorus-Containing Extended Transition State Analog Inhibitors of Metalloaminopeptidases
Janiszewska, K.; Talma, M.; Oszywa, B.; Pawełczak, M.; Kafarski, P.; Mucha, A.,
Molecules 2020, 25, 4334
DOI: 10.3390/molecules25184334

Peptidyl enzyme inhibitors containing an internal aminomethylphosphinic bond system (P(O)(OH)-CH2-NH) can be termed extended transition state analogs by similarity to the corresponding phosphonamidates (P(O)(OH)-NH). Phosphonamidate pseudopeptides are broadly recognized as competitive mechanism-based inhibitors of metalloenzymes, mainly hydrolases. Their practical use is, however, limited by hydrolytic instability, which is particularly restricting for dipeptide analogs. Extension of phosphonamidates by addition of the methylene group produces a P-C-N system fully resistant in water conditions. In the current work, we present a versatile synthetic approach to such modified dipeptides, based on the three-component phospha-Mannich condensation of phosphinic acids, formaldehyde, and N-benzylglycines. The last-mentioned component allowed for simple and versatile introduction of functionalized P1' residues located on the tertiary amino group. The products demonstrated moderate inhibitory activity towards porcine and plant metalloaminopeptidases, while selected derivatives appeared very potent with human alanyl aminopeptidase (Ki = 102 nM for 6a). Analysis of ligand-protein complexes obtained by molecular modelling revealed canonical modes of interactions for mono-metallic alanyl aminopeptidases, and distorted modes for di-metallic leucine aminopeptidases (with C-terminal carboxylate, not phosphinate, involved in metal coordination). In general, the method can be dedicated to examine P1'-S1' complementarity in searching for non-evident structures of specific residues as the key fragments of perspective ligands.

Recent papers

Systematic ‘foldamerization’ of peptide inhibiting p53-MDM2/X interactions by the incorporation of trans- or cis-2-aminocyclopentanecarboxylic acid residues
Fortuna, P.; Twarda-Clapa, A.; Skalniak, L.; Ożga, K.; Holak, T. A.; Berlicki, Ł.
Eur. J. Med. Chem. 2020, 208, 112814
DOI: 10.1016/j.ejmech.2020.112814

A ‘foldamerization’ strategy for the discovery of biologically active peptide is evaluated using as an example the peptides that inhibit the p53-MDM2/X interactions. Application of a peptide scan with two constrained β-residue of trans and cis stereochemistry indicated a substitution pattern that leads to active molecules with enhanced conformational stability and high resistance to proteolysis. This procedure led to the discovery of a peptide that showed subnanomolar inhibition of the p53-MDM2 interaction (Ki = 0.4 nM) with resistance to proteolysis enhanced by ca. two orders of magnitude. Crystallographic analysis and molecular modelling allowed for understanding of these peptide-protein interactions at the molecular level.