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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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Opublikowany przez Berlicki Lab Poniedziałek, 27 lipca 2020

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.

Recent papers

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases
Wanat, W. ; Talma, M.; Dziuk, B.; Kafarski, P
Biomolecules 2020, 10, 1
DOI: 10.3390/biom10091319

A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine(pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzymeinhibitor complexes for hAPN and pAPN were determined.

Recent papers

Covalent and noncovalent constraints yield a figure eight-like conformation of a peptide inhibiting the menin-MLL interaction
Fortuna, P.; Linhares, B. M.; Purohit, T.; Pollock, J.; Cierpicki, T.; Grembecka, J.; Berlicki, Ł.
Eur. J. Med. Chem. 2020, 207, 112748
DOI: 10.1016/j.ejmech.2020.112748

The interaction between menin and mixed lineage leukemia (MLL) was identified as an interesting target for treating some cancers including acute leukemia. On the basis of the known crystal structure of the MBM1-menin complex (MBM - menin binding motif), several cyclic peptides were designed. Elaboration of the effective cyclization strategy using a metathesis reaction allowed for a successfully large number of derivatives to be obtained. Subsequent optimization of the loop size, as well as N-terminal, central and C-terminal parts of the studied peptides resulted in structures exhibiting low nanomolar activities. A crystal structure of an inhibitor-menin complex revealed a compact conformation of the ligand molecule, which is stabilized not only by the introduction of a covalent linker but also three intramolecular hydrogen bonds. The inhibitor adopts a figure eight-like conformation, which perfectly fits the cleft of menin. We demonstrated that the development of compact, miniprotein-like structures is a highly effective approach for inhibition of protein-protein interactions.

Recent papers

Phosphonopeptides containing free phosphonic groups: recent advances
Kafarski, P.
RCS Adv. 2020, 10, 25898
DOI: 10.1039/d0ra04655h

Phosphonopeptides are mimetics of peptides in which phosphonic acid or related (phosphinic, phosphonous etc.) group replaces either carboxylic acid group present at C-terminus, is located in the peptidyl side chain, or phosphonamidate or phosphinic acid mimics peptide bond. Acting as inhibitors of key enzymes related to variable pathological states they display interesting and useful physiologic activities with potential applications in medicine and agriculture. Since the synthesis and biological properties of peptides containing C-terminal diaryl phosphonates and those with phosphonic fragment replacing peptide bond were comprehensively reviewed, this review concentrate on peptides holding free, unsubstituted phosphonic acid moiety. There are two groups of such mimetics: (i) peptides in which aminophosphonic acid is located at C-terminus of the peptide chain with most of them (including antibiotics isolated from bacteria and fungi) exhibiting antimicrobial activity; (ii) non-hydrolysable analogues of phosphonoamino acids, which are useful tools to study physiologic effects of phosphorylations.

Recent papers

Nuclear immunophilin FKBP39 from Drosophila melanogaster drives spontaneous liquid-liquid phase separation.
Tarczewska, A.; Wycisk, K.; Orłowski, M.;Waligórska, A.; Dobrucki, J.; Drewniak-Świtalska, M.; Berlicki, Ł.; Ożyhar, A.
Int. J. Biol. Macromol. 2020, 163, 108
DOI: 10.1016/j.ijbiomac.2020.06.255
The FKBP39 from Drosophila melanogaster is a multifunctional regulatory immunophilin. It contains two globular domains linked by a highly charged disordered region. The N-terminal domain shows homology to the nucleoplasmin core domain, and the C-terminal domain is characteristic for the family of the FKBP immunophilin ligand binding domain. The specific partially disordered structure of the protein inspired us to investigate whether FKBP39 can drive spontaneous liquid-liquid phase separation (LLPS). Preliminary analyses using CatGranule and Pi-Pi contact predictors suggested a propensity for LLPS. Microscopy observations revealed that FKBP39 can self-concentrate to form liquid condensates. We also found that FKBP39 can lead to LLPS in the presence of RNA and peptides containing Arg-rich linear motifs derived from selected nuclear and nucleolar proteins. These heterotypic interactions have a stronger propensity for driving LLPS when compared to the interactions mediated by self-associating FKBP39 molecules. To investigate whether FKBP39 can drive LLPS in the cellular environment, we analysed it in fusion with YFP in COS-7 cells. The specific distribution and diffusion kinetics of FKBP39 examined by FRAP experiments provided evidence that immunophilin is an important driver of phase separation. The ability of FKBP39 to go into heterotypic interaction may be fundamental for ribosome subunits assembly.