TY - JOUR AU - Olajos, Gábor AU - Hetényi, Anasztázia AU - Wéber, Edit AU - Németh, Lukács AU - Szakonyi, Zsolt AU - Fülöp, Ferenc AU - Martinek, Tamás TI - Induced Folding of Protein-Sized Foldameric β-Sandwich Models with Core β-Amino Acid Residues JF - CHEMISTRY-A EUROPEAN JOURNAL J2 - CHEM-EUR J VL - 21 PY - 2015 IS - 16 SP - 6173 EP - 6180 PG - 8 SN - 0947-6539 DO - 10.1002/chem.201405581 UR - https://m2.mtmt.hu/api/publication/2868602 ID - 2868602 N1 - Funding Agency and Grant Number: Hungarian Academy of Sciences (Lendulet program) [LP-2011-009]; Gedeon Richter Plc. [TP7-017]; Hungarian Research Foundation [OTKA K112442]\n Funding text: This work was supported by the Hungarian Academy of Sciences (Lendulet program LP-2011-009), Gedeon Richter Plc. (TP7-017), and the Hungarian Research Foundation (OTKA K112442). Computations were carried out at the HPC Center of the University of Szeged (TAMOP-4.2.2.C-11/1/KONV-2012-0010).\n Funding Agency and Grant Number: Hungarian Academy of Sciences (Lendulet program) [LP-2011-009]; Gedeon Richter Plc. [TP7-017]; Hungarian Research FoundationOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA K112442] Funding text: This work was supported by the Hungarian Academy of Sciences (Lendulet program LP-2011-009), Gedeon Richter Plc. (TP7-017), and the Hungarian Research Foundation (OTKA K112442). Computations were carried out at the HPC Center of the University of Szeged (TAMOP-4.2.2.C-11/1/KONV-2012-0010). CAplus AN 2015:484036; MEDLINE PMID: 25677195 (Journal; Article; Research Support, Non-U.S. Gov't); AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Cabrele, C AU - Martinek, Tamás AU - Reiser, O AU - Berlicki, Ł TI - Peptides containing β-amino acid patterns: Challenges and successes in medicinal chemistry JF - JOURNAL OF MEDICINAL CHEMISTRY J2 - J MED CHEM VL - 57 PY - 2014 IS - 23 SP - 9718 EP - 9739 PG - 22 SN - 0022-2623 DO - 10.1021/jm5010896 UR - https://m2.mtmt.hu/api/publication/2817673 ID - 2817673 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Keserű, György Miklós AU - Soós, Tibor AU - Kappe, CO TI - Anthropogenic reaction parameters - the missing link between chemical intuition and the available chemical space JF - CHEMICAL SOCIETY REVIEWS J2 - CHEM SOC REV VL - 43 PY - 2014 SP - 5387 EP - 5399 PG - 13 SN - 0306-0012 DO - 10.1039/C3CS60423C UR - https://m2.mtmt.hu/api/publication/2701748 ID - 2701748 LA - English DB - MTMT ER - TY - JOUR AU - Mándity, István AU - Olasz, Balázs AU - Ötvös, Sándor Balázs AU - Fülöp, Ferenc TI - Continuous-Flow Solid-Phase Peptide Synthesis: A Revolutionary Reduction of the Amino Acid Excess JF - CHEMSUSCHEM J2 - CHEMSUSCHEM VL - 7 PY - 2014 IS - 11 SP - 3172 EP - 3176 PG - 5 SN - 1864-5631 DO - 10.1002/cssc.201402436 UR - https://m2.mtmt.hu/api/publication/2730808 ID - 2730808 N1 - Funding Agency and Grant Number: Hungarian Research FoundationOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA NK81371, PD103994]; TAMOP [4.2.2/B-10/1-2010-0012]; Hungarian Academy of SciencesHungarian Academy of Sciences Funding text: We are grateful to the Hungarian Research Foundation (OTKA NK81371 and PD103994) and TAMOP 4.2.2/B-10/1-2010-0012. I. M. M. acknowledges the award of a Janos Bolyai scholarship from the Hungarian Academy of Sciences. ISSN:1864-5631 LA - English DB - MTMT ER - TY - JOUR AU - Hegedüs, Zsófia AU - Wéber, Edit AU - Kriston-Pál, Éva AU - Makra, Ildikó AU - Czibula, Ágnes AU - Monostori, Éva AU - Martinek, Tamás TI - Foldameric α/β-Peptide Analogs of the β-Sheet-Forming Antiangiogenic Anginex: Structure and Bioactivity JF - JOURNAL OF THE AMERICAN CHEMICAL SOCIETY J2 - J AM CHEM SOC VL - 135 PY - 2013 IS - 44 SP - 16578 EP - 16584 PG - 7 SN - 0002-7863 DO - 10.1021/ja408054f UR - https://m2.mtmt.hu/api/publication/2459240 ID - 2459240 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Fülöp, Lívia AU - Mándity, István AU - Juhász, Gábor AU - Szegedi, Viktor AU - Hetényi, Anasztázia AU - Wéber, Edit AU - Bozsó, Zsolt AU - Simon, Dóra AU - Benkő, Mária AU - Király, Zoltán AU - Martinek, Tamás TI - A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic Beta-Amyloid Oligomers JF - PLOS ONE J2 - PLOS ONE VL - 7 PY - 2012 IS - 7 PG - 17 SN - 1932-6203 DO - 10.1371/journal.pone.0039485 UR - https://m2.mtmt.hu/api/publication/2034805 ID - 2034805 N1 - Funding Agency and Grant Number: EU FP7 [HEALTH-F2-2007-201159, HEALTH-F2-2007-211696]; COST [CM0803]; Hungarian Research Foundation [NK81371, PD83581, PD83600, K68152]; Hungarian Academy of Sciences, Lendulet programme\n Funding text: This work was supported by the EU FP7 (HEALTH-F2-2007-201159, HEALTH-F2-2007-211696 and COST CM0803) (http://cordis.europa.eu/fp7/home_en.html); the Hungarian Research Foundation (NK81371, PD83581, PD83600 and K68152) (http://www.otka.hu/); and the Hungarian Academy of Sciences, Lendulet programme (http://mta.hu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n Department of Medical Chemistry, University of Szeged, Szeged, Hungary Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary Bay Zoltán Foundation for Applied Research - BAYGEN, Szeged, Hungary Department of Physical Chemistry and Materials Science, University of Szeged, Szeged, Hungary Cited By :31 Export Date: 24 April 2020 Correspondence Address: Martinek, T. A.; Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary; email: martinek@pharm.u-szeged.hu Chemicals/CAS: amyloid beta protein, 109770-29-8; Amyloid beta-Peptides; Dendrimers CAplus AN 2012:1144372; MEDLINE PMID: 22859942 (Journal; Article; Research Support, Non-U.S. Gov't); AB - 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.

 LA - English DB - MTMT ER - TY - JOUR AU - Martinek, Tamás AU - Fülöp, Ferenc TI - Peptidic foldamers: ramping up diversity JF - CHEMICAL SOCIETY REVIEWS J2 - CHEM SOC REV VL - 41 PY - 2012 IS - 2 SP - 687 EP - 702 PG - 16 SN - 0306-0012 DO - 10.1039/c1cs15097a UR - https://m2.mtmt.hu/api/publication/1842290 ID - 1842290 N1 - Funding Agency and Grant Number: Hungarian Research FoundationOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [NK81371, K83882, TAMOP-4.2.1/B-09/1/KONV-2010-0005]; COSTEuropean Cooperation in Science and Technology (COST) [CM0803]; Janos Bolyai FellowshipHungarian Academy of Sciences; HAS [LP2011-009/2011] Funding text: We thank the Hungarian Research Foundation (NK81371 and K83882), TAMOP-4.2.1/B-09/1/KONV-2010-0005 and COST (CM0803) for financial support. T.A.M. acknowledges the Janos Bolyai Fellowship and the "Lendulet'' programme (LP2011-009/2011) from the HAS. CAplus AN 2012:19612; MEDLINE PMID: 21769415 (Journal; General Review; Article; Research Support, Non-U.S. Gov't; Review); AB - 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). LA - English DB - MTMT ER - TY - JOUR AU - Mándity, István AU - Fülöp, Lívia AU - Vass, Elemér AU - Tóth, Gábor AU - Martinek, Tamás AU - Fülöp, Ferenc TI - Building β-Peptide H10/12 Foldamer Helices with Six-Membered Cyclic Side-Chains: Fine-Tuning of Folding and Self-Assembly JF - ORGANIC LETTERS J2 - ORG LETT VL - 12 PY - 2010 IS - 23 SP - 5584 EP - 5587 PG - 4 SN - 1523-7060 DO - 10.1021/ol102494m UR - https://m2.mtmt.hu/api/publication/1412123 ID - 1412123 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Mándity, István AU - Wéber, Edit AU - Martinek, Tamás AU - Olajos, Gábor AU - Tóth, Gábor AU - Vass, Elemér AU - Fülöp, Ferenc TI - Design of Peptidic Foldamer Helices: A Stereochemical Patterning Approach JF - ANGEWANDTE CHEMIE-INTERNATIONAL EDITION J2 - ANGEW CHEM INT EDIT VL - 48 PY - 2009 IS - 12 SP - 2171 EP - 2175 PG - 5 SN - 1433-7851 DO - 10.1002/anie.200805095 UR - https://m2.mtmt.hu/api/publication/1232853 ID - 1232853 N1 - Institutes of Pharmaceutical Chemistry and Medical Chemistry, Universitiy of Szeged, Etvs u. 6, 6720 Szeged, Hungary Department of Organic Chemistry, Etvs Loránd University, Pázmány P. s. 1A, 1117 Budapest, Hungary Cited By :101 Export Date: 5 April 2024 CODEN: ACIEA Correspondence Address: Mándity, I. M.; Institutes of Pharmaceutical Chemistry and Medical Chemistry, Etvs u. 6, 6720 Szeged, Hungary LA - English DB - MTMT ER - TY - JOUR AU - Fülöp, Ferenc AU - Martinek, Tamás AU - Tóth, Gábor TI - Application of alicyclic beta-amino acids in peptide chemistry JF - CHEMICAL SOCIETY REVIEWS J2 - CHEM SOC REV VL - 35 PY - 2006 IS - 4 SP - 323 EP - 334 PG - 12 SN - 0306-0012 DO - 10.1039/B501173F UR - https://m2.mtmt.hu/api/publication/1012938 ID - 1012938 N1 - Megjegyzés-21956224 Z9: 133 WC: Chemistry, Multidisciplinary Megjegyzés-21957808 Z9: 133 WC: Chemistry, Multidisciplinary CAplus AN 2006:279672; MEDLINE PMID: 16565749 (Journal; General Review; Article; Research Support, Non-U.S. Gov't; Review); AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Martinek, Tamás AU - Mándity, István AU - Fülöp, Lívia AU - Tóth, Gábor AU - Vass, Elemér AU - Hollósi, Miklós AU - Forró, Enikő AU - Fülöp, Ferenc TI - Effects of the alternating backbone configuration on the secondary structure and self-assembly of beta-peptides JF - JOURNAL OF THE AMERICAN CHEMICAL SOCIETY J2 - J AM CHEM SOC VL - 128 PY - 2006 IS - 41 SP - 13539 EP - 13544 PG - 6 SN - 0002-7863 DO - 10.1021/ja063890c UR - https://m2.mtmt.hu/api/publication/1078988 ID - 1078988 AB - 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. LA - English DB - MTMT ER -