TY - JOUR AU - Hetényi, Anasztázia AU - Németh, Lukács AU - Wéber, Edit AU - Szakonyi, Gerda AU - Winter, Zoltán AU - Jósvay, Katalin AU - Bartus, Éva AU - Oláh, Zoltán AU - Martinek, Tamás TI - Competitive inhibition of TRPV1 – calmodulin interaction by vanilloids JF - FEBS LETTERS J2 - FEBS LETT VL - 590 PY - 2016 IS - 16 SP - 2768 EP - 2775 PG - 8 SN - 0014-5793 DO - 10.1002/1873-3468.12267 UR - https://m2.mtmt.hu/api/publication/3087152 ID - 3087152 N1 - Funding Agency and Grant Number: Hungarian Academy of Sciences; Lendulet Program [LP-2011-009]; MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. [TP7-017]; Hungarian Research Foundation [OTKA K112442]; Richter Gedeon Talentum Alapitvany; European Union; State of Hungary; European Social Fund [TAMOP-4.2.4.A/ 2-11/1-2012-0001]\n Funding text: This work was supported by the Hungarian Academy of Sciences, Lendulet Program (LP-2011-009), MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. (TP7-017), the Hungarian Research Foundation (OTKA K112442) and Financial support from Richter Gedeon Talentum Alapitvany (Ph.D. Scholarship to E.B.). This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP-4.2.4.A/ 2-11/1-2012-0001 'National Excellence Program'.\n Funding Agency and Grant Number: Hungarian Academy of Sciences; Lendulet Program [LP-2011-009]; MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. [TP7-017]; Hungarian Research Foundation [OTKA K112442]; Richter Gedeon Talentum Alapitvany; European Union; State of Hungary; European Social Fund [TAMOP-4.2.4.A/ 2-11/1-2012-0001] Funding text: This work was supported by the Hungarian Academy of Sciences, Lendulet Program (LP-2011-009), MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. (TP7-017), the Hungarian Research Foundation (OTKA K112442) and Financial support from Richter Gedeon Talentum Alapitvany (Ph.D. Scholarship to E.B.). This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP-4.2.4.A/ 2-11/1-2012-0001 'National Excellence Program'. AB - There is enormous interest toward vanilloid agonists of the pain receptor TRPV1 in analgesic therapy, but the mechanisms of their sensory neuron-blocking effects at high or repeated doses are still a matter of debate. Our results have demonstrated that capsaicin and resiniferatoxin form nanomolar complexes with calmodulin, and competitively inhibit TRPV1-calmodulin interaction. These interactions involve the protein recognition interface of calmodulin, which is responsible for all of the cell-regulatory calmodulin-protein interactions. These results draw attention to a previously unknown vanilloid target, which may contribute to the explanation of the paradoxical pain-modulating behavior of these important pharmacons. 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 - 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 -