@article{MTMT:2868602, title = {Induced Folding of Protein-Sized Foldameric β-Sandwich Models with Core β-Amino Acid Residues}, url = {https://m2.mtmt.hu/api/publication/2868602}, author = {Olajos, Gábor and Hetényi, Anasztázia and Wéber, Edit and Németh, Lukács and Szakonyi, Zsolt and Fülöp, Ferenc and Martinek, Tamás}, doi = {10.1002/chem.201405581}, journal-iso = {CHEM-EUR J}, journal = {CHEMISTRY-A EUROPEAN JOURNAL}, volume = {21}, unique-id = {2868602}, issn = {0947-6539}, abstract = {The mimicry of protein-sized β-sheet structures with unnatural peptidic sequences (foldamers) is a considerable challenge. In this work, the de novo designed betabellin-14 β-sheet has been used as a template, and α→β residue mutations were carried out in the hydrophobic core (positions 12 and 19). β-Residues with diverse structural properties were utilized: Homologous β3-amino acids, (1R,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (1R,2S)-2-aminocyclohexanecarboxylic acid (ACHC), (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (ACEC), and (1S,2S,3R,5S)-2-amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylic acid (ABHC). Six α/β-peptidic chains were constructed in both monomeric and disulfide-linked dimeric forms. Structural studies based on circular dichroism spectroscopy, the analysis of NMR chemical shifts, and molecular dynamics simulations revealed that dimerization induced β-sheet formation in the 64-residue foldameric systems. Core replacement with (1R,2S)-ACHC was found to be unique among the β-amino acid building blocks studied because it was simultaneously able to maintain the interstrand hydrogen-bonding network and to fit sterically into the hydrophobic interior of the β-sandwich. The novel β-sandwich model containing 25% unnatural building blocks afforded protein-like thermal denaturation behavior. Dissolving sandwiches: A water-soluble β-sandwich has been constructed by using cyclic β-amino acids in the hydrophobic core (see figure). The structural stability is highly dependent on the side-chain, and the destructuring effects of the β-residues could be minimized by using (1R,2S)-2-aminocyclohexanecarboxylic acid. The β-sandwich displays protein-like thermal denaturation behavior.}, keywords = {PROTEINS; STABILITY; Protein Folding; Chemical bonds; amino acids; PEPTIDOMIMETICS; DICHROISM; molecular dynamics; chemical analysis; DYES; Hydrophobicity; Hydrogen bonds; molecular dynamics simulations; CHAINS; circular dichroism spectroscopy; Structural stabilities; Protein Engineering; Thermal denaturations; Hydrogen bonding network; NMR chemical shifts; PROTEIN STRUCTURES}, year = {2015}, eissn = {1521-3765}, pages = {6173-6180}, orcid-numbers = {Olajos, Gábor/0000-0002-2479-4891; Hetényi, Anasztázia/0000-0001-8080-6992; Wéber, Edit/0000-0002-5904-0619; Szakonyi, Zsolt/0000-0003-2432-8409; Fülöp, Ferenc/0000-0003-1066-5287; Martinek, Tamás/0000-0003-3168-8066} } @article{MTMT:2817673, title = {Peptides containing β-amino acid patterns: Challenges and successes in medicinal chemistry}, url = {https://m2.mtmt.hu/api/publication/2817673}, author = {Cabrele, C and Martinek, Tamás and Reiser, O and Berlicki, Ł}, doi = {10.1021/jm5010896}, journal-iso = {J MED CHEM}, journal = {JOURNAL OF MEDICINAL CHEMISTRY}, volume = {57}, unique-id = {2817673}, issn = {0022-2623}, abstract = {The construction of bioactive peptides using β-amino acid-containing sequence patterns is a very promising strategy to obtain analogues that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of native peptides. They can be either combined with α-amino acids by following specific patterns, which results in backbone architectures with well-defined orientations of the side chain functional groups, or assembled in de novo-designed bioactive β- or α,β-peptidic sequences. Such peptides display various biological functions, including antimicrobial activity, inhibition of protein-protein interactions, agonism/antagonism of GPCR ligands, and anti-angiogenic activity.}, year = {2014}, eissn = {1520-4804}, pages = {9718-9739}, orcid-numbers = {Martinek, Tamás/0000-0003-3168-8066} } @article{MTMT:2701748, title = {Anthropogenic reaction parameters - the missing link between chemical intuition and the available chemical space}, url = {https://m2.mtmt.hu/api/publication/2701748}, author = {Keserű, György Miklós and Soós, Tibor and Kappe, CO}, doi = {10.1039/C3CS60423C}, journal-iso = {CHEM SOC REV}, journal = {CHEMICAL SOCIETY REVIEWS}, volume = {43}, unique-id = {2701748}, issn = {0306-0012}, year = {2014}, eissn = {1460-4744}, pages = {5387-5399} } @article{MTMT:2730808, title = {Continuous-Flow Solid-Phase Peptide Synthesis: A Revolutionary Reduction of the Amino Acid Excess}, url = {https://m2.mtmt.hu/api/publication/2730808}, author = {Mándity, István and Olasz, Balázs and Ötvös, Sándor Balázs and Fülöp, Ferenc}, doi = {10.1002/cssc.201402436}, journal-iso = {CHEMSUSCHEM}, journal = {CHEMSUSCHEM}, volume = {7}, unique-id = {2730808}, issn = {1864-5631}, year = {2014}, eissn = {1864-564X}, pages = {3172-3176}, orcid-numbers = {Mándity, István/0000-0003-2865-6143; Olasz, Balázs/0000-0003-4132-0054; Ötvös, Sándor Balázs/0000-0001-6673-1744; Fülöp, Ferenc/0000-0003-1066-5287} } @article{MTMT:2459240, title = {Foldameric α/β-Peptide Analogs of the β-Sheet-Forming Antiangiogenic Anginex: Structure and Bioactivity}, url = {https://m2.mtmt.hu/api/publication/2459240}, author = {Hegedüs, Zsófia and Wéber, Edit and Kriston-Pál, Éva and Makra, Ildikó and Czibula, Ágnes and Monostori, Éva and Martinek, Tamás}, doi = {10.1021/ja408054f}, journal-iso = {J AM CHEM SOC}, journal = {JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, volume = {135}, unique-id = {2459240}, issn = {0002-7863}, abstract = {The principles of beta-sheet folding and design for alpha-peptidic sequences are well established, while those for sheet mimetics containing homologated amino acid building blocks are still under investigation. To reveal the structure-function relations of beta-amino-acid-containing foldamers, we followed a top-down approach to study a series of alpha/beta-peptidic analogs of anginex, a beta-sheet-forming antiangiogenic peptide. Eight anginex analogs were developed by systematic alpha --> beta(3) substitutions and analyzed by using NMR and CD spectroscopy. The foldamers retained the beta-sheet tendency, though with a decreased folding propensity. beta-Sheet formation could be induced by a micellar environment, similarly to that of the parent peptide. The destructuring effect was higher when the alpha --> beta(3) exchange was located in the beta-sheet core. Analysis of the beta-sheet stability versus substitution pattern and the local conformational bias of the bulky beta(3)V and beta(3)I residues revealed that a mismatch between the H-bonding preferences of the alpha- and beta-residues played a minor role in the structure-breaking effect. Temperature-dependent CD and NMR measurements showed that the hydrophobic stabilization was scaled-down for the alpha/beta-peptides. Analysis of the biological activity of the foldamer peptides showed that four anginex derivatives dose-dependently inhibited the proliferation of a mouse endothelial cell line. The alpha --> beta(3) substitution strategy applied in this work can be a useful approach to the construction of bioactive beta-sheet mimetics with a reduced aggregation tendency and improved pharmacokinetic properties.}, year = {2013}, eissn = {1520-5126}, pages = {16578-16584}, orcid-numbers = {Hegedüs, Zsófia/0000-0002-5546-8167; Wéber, Edit/0000-0002-5904-0619; Czibula, Ágnes/0000-0003-4461-2773; Monostori, Éva/0000-0002-7442-3562; Martinek, Tamás/0000-0003-3168-8066} } @article{MTMT:2034805, title = {A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic Beta-Amyloid Oligomers}, url = {https://m2.mtmt.hu/api/publication/2034805}, author = {Fülöp, Lívia and Mándity, István and Juhász, Gábor and Szegedi, Viktor and Hetényi, Anasztázia and Wéber, Edit and Bozsó, Zsolt and Simon, Dóra and Benkő, Mária and Király, Zoltán and Martinek, Tamás}, doi = {10.1371/journal.pone.0039485}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {7}, unique-id = {2034805}, issn = {1932-6203}, abstract = {Background and Aims

Unnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge.

Methods and Results

Short helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration.

Conclusions

The combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target.

}, keywords = {Neurotoxicity; hippocampus; ARTICLE; MOUSE; controlled study; nonhuman; animal tissue; Protein Binding; in vitro study; POLYMER; unclassified drug; binding affinity; chemical structure; Biophysics; BIOCHEMISTRY; ex vivo study; Oligomer; Nuclear magnetic resonance spectroscopy; protein interaction; amyloid beta protein; chemical binding; long term potentiation; dendrimer; foldamer}, year = {2012}, eissn = {1932-6203}, orcid-numbers = {Fülöp, Lívia/0000-0002-8010-0129; Mándity, István/0000-0003-2865-6143; Szegedi, Viktor/0000-0003-4191-379X; Hetényi, Anasztázia/0000-0001-8080-6992; Wéber, Edit/0000-0002-5904-0619; Bozsó, Zsolt/0000-0002-5713-3096; Martinek, Tamás/0000-0003-3168-8066} } @article{MTMT:1842290, title = {Peptidic foldamers: ramping up diversity}, url = {https://m2.mtmt.hu/api/publication/1842290}, author = {Martinek, Tamás and Fülöp, Ferenc}, doi = {10.1039/c1cs15097a}, journal-iso = {CHEM SOC REV}, journal = {CHEMICAL SOCIETY REVIEWS}, volume = {41}, unique-id = {1842290}, issn = {0306-0012}, abstract = {Non-natural folded polymers (foldamers) display considerable versatility, and the design of such molecules is of great current interest. In this respect, peptidic foldamers are perhaps the best-characterized systems, as they populate a number of residue-controlled secondary structures, which have found various biological applications and have also led to the creation of nanostructured materials. This critical review covers recent developments related to diverse building blocks and modern foldamer design principles, such as the stereochemical patterning methods. The recent achievements concerning tertiary/quaternary structures and the self-assembling foldameric nanostructures are also addressed (176 references).}, keywords = {DE-NOVO DESIGN; BETA-AMINO ACIDS; PROTEINOGENIC SIDE-CHAINS; MODEL SYNTHETIC FOLDAMERS; GCN4 LEUCINE-ZIPPER; HYDROGEN-BONDED RINGS; PARALLEL SHEET STRUCTURE; MIXED ALPHA/BETA-PEPTIDES; HELICAL SECONDARY STRUCTURES; EFFECTIVE SIMULATION PROTOCOLS}, year = {2012}, eissn = {1460-4744}, pages = {687-702}, orcid-numbers = {Martinek, Tamás/0000-0003-3168-8066; Fülöp, Ferenc/0000-0003-1066-5287} } @article{MTMT:1412123, title = {Building β-Peptide H10/12 Foldamer Helices with Six-Membered Cyclic Side-Chains: Fine-Tuning of Folding and Self-Assembly}, url = {https://m2.mtmt.hu/api/publication/1412123}, author = {Mándity, István and Fülöp, Lívia and Vass, Elemér and Tóth, Gábor and Martinek, Tamás and Fülöp, Ferenc}, doi = {10.1021/ol102494m}, journal-iso = {ORG LETT}, journal = {ORGANIC LETTERS}, volume = {12}, unique-id = {1412123}, issn = {1523-7060}, abstract = {The ability of the beta-peptidic H10/12 helix to tolerate side-chains containing six-membered alicyclic rings was studied. cis-2-Aminocyclohex-3-ene carboxylic acid (cis-ACHEC) res dues afforded H10/12 helix formation with alternating backbone configuration. Conformational polymorphism was observed for the alternating cis-ACHC hexamer, where chemical exchange takes place between the major left-handed H10/12 helix and a minor folded conformation. The hydrophobically driven self-assembly was achieved for the cis-ACHC-containing helix which was observed as vesicles similar to 100 nm in diameter.}, keywords = {ASSOCIATION; FAMILY; DESIGN; SECONDARY STRUCTURE; NMR; OLIGOMERS; amino acids; CD; LYOTROPIC LIQUID-CRYSTALS}, year = {2010}, eissn = {1523-7052}, pages = {5584-5587}, orcid-numbers = {Mándity, István/0000-0003-2865-6143; Fülöp, Lívia/0000-0002-8010-0129; Vass, Elemér/0000-0001-8898-3846; Tóth, Gábor/0000-0002-3604-4385; Martinek, Tamás/0000-0003-3168-8066; Fülöp, Ferenc/0000-0003-1066-5287} } @article{MTMT:1232853, title = {Design of Peptidic Foldamer Helices: A Stereochemical Patterning Approach}, url = {https://m2.mtmt.hu/api/publication/1232853}, author = {Mándity, István and Wéber, Edit and Martinek, Tamás and Olajos, Gábor and Tóth, Gábor and Vass, Elemér and Fülöp, Ferenc}, doi = {10.1002/anie.200805095}, journal-iso = {ANGEW CHEM INT EDIT}, journal = {ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}, volume = {48}, unique-id = {1232853}, issn = {1433-7851}, keywords = {SEQUENCES; SECONDARY STRUCTURE; CONFORMATIONS; DE-NOVO DESIGN; PROTEINOGENIC SIDE-CHAINS; FOLDAMERS; OLIGOMERS; amino acids; NMR spectroscopy; ALPHA/BETA-PEPTIDES; helical structures; BETA-AMINO-ACID; BETA(3)-PEPTIDES}, year = {2009}, eissn = {1521-3773}, pages = {2171-2175}, orcid-numbers = {Mándity, István/0000-0003-2865-6143; Wéber, Edit/0000-0002-5904-0619; Martinek, Tamás/0000-0003-3168-8066; Olajos, Gábor/0000-0002-2479-4891; Tóth, Gábor/0000-0002-3604-4385; Vass, Elemér/0000-0001-8898-3846; Fülöp, Ferenc/0000-0003-1066-5287} } @article{MTMT:1012938, title = {Application of alicyclic beta-amino acids in peptide chemistry}, url = {https://m2.mtmt.hu/api/publication/1012938}, author = {Fülöp, Ferenc and Martinek, Tamás and Tóth, Gábor}, doi = {10.1039/B501173F}, journal-iso = {CHEM SOC REV}, journal = {CHEMICAL SOCIETY REVIEWS}, volume = {35}, unique-id = {1012938}, issn = {0306-0012}, abstract = {The self-organizing beta-peptides have attracted considerable interest in the fields of foldamer chemistry and biochemistry. These compounds exhibit various stable secondary structure motifs that can be exploited to construct biologically active substances and nanostructured tertiary structures. The secondary structures can be controlled via the beta-amino acid sequence, and cyclic beta-amino acid residues play a crucial role in the design. The most important procedures for the preparation of cyclic beta-amino acid monomers and peptides are discussed in this tutorial review. Besides the secondary structure design principles, the methods of folded structure detection are surveyed.}, keywords = {DERIVATIVES; TRANSFORMATION; STEREOSELECTIVE-SYNTHESIS; HELIX; OLIGOMERS; DESIGN PRINCIPLES; TRANS-2-AMINOCYCLOPENTANECARBOXYLIC ACID; SELF-ASSOCIATION; DESYMMETRIZATION}, year = {2006}, eissn = {1460-4744}, pages = {323-334}, orcid-numbers = {Fülöp, Ferenc/0000-0003-1066-5287; Martinek, Tamás/0000-0003-3168-8066; Tóth, Gábor/0000-0002-3604-4385} } @article{MTMT:1078988, title = {Effects of the alternating backbone configuration on the secondary structure and self-assembly of beta-peptides}, url = {https://m2.mtmt.hu/api/publication/1078988}, author = {Martinek, Tamás and Mándity, István and Fülöp, Lívia and Tóth, Gábor and Vass, Elemér and Hollósi, Miklós and Forró, Enikő and Fülöp, Ferenc}, doi = {10.1021/ja063890c}, journal-iso = {J AM CHEM SOC}, journal = {JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, volume = {128}, unique-id = {1078988}, issn = {0002-7863}, abstract = {Heterochiral homo-oligomers with alternating backbone configurations were constructed by using the different enantiomers of the cis- and trans-2-aminocyclopentanecarboxylic acid (ACPC) monomers. Molecular modeling and the spectroscopic techniques (NMR, ECD, and VCD) unequivocally proved that the alternating heterochiral cis-ACPC sequences form an H10/12 helix, where extra stabilization can be achieved via the cyclic side chains. The ECD and TEM measurements, together with molecular modeling, revealed that the alternating heterochiral trans-ACPC oligomers tend to attain a polar-strand secondary structure in solution, which can self-assemble into nanostructured fibrils. The observations indicate that coverage of all the possible secondary structures (various helix types and strand-mimicking conformations) can be attained with the help of cyclic beta-amino acid diastereomers. A relationship has been established between the backbone chirality pattern and the prevailing secondary structure, which underlines the role of stereochemical control in the beta-peptide secondary structure design and may contribute to future biological applications.}, keywords = {SIDE-CHAINS; FOLDAMERS; OLIGOMERS; DESIGN PRINCIPLES; AMINO-ACID; CHIRAL MOLECULES; VIBRATIONAL CIRCULAR-DICHROISM; SHORT ALPHA/BETA-PEPTIDES; HELICAL CONFORMATIONS}, year = {2006}, eissn = {1520-5126}, pages = {13539-13544}, orcid-numbers = {Martinek, Tamás/0000-0003-3168-8066; Mándity, István/0000-0003-2865-6143; Fülöp, Lívia/0000-0002-8010-0129; Tóth, Gábor/0000-0002-3604-4385; Vass, Elemér/0000-0001-8898-3846; Forró, Enikő/0000-0001-6796-3889; Fülöp, Ferenc/0000-0003-1066-5287} }