@article{MTMT:3087152, title = {Competitive inhibition of TRPV1 – calmodulin interaction by vanilloids}, url = {https://m2.mtmt.hu/api/publication/3087152}, author = {Hetényi, Anasztázia and Németh, Lukács and Wéber, Edit and Szakonyi, Gerda and Winter, Zoltán and Jósvay, Katalin and Bartus, Éva and Oláh, Zoltán and Martinek, Tamás}, doi = {10.1002/1873-3468.12267}, journal-iso = {FEBS LETT}, journal = {FEBS LETTERS}, volume = {590}, unique-id = {3087152}, issn = {0014-5793}, abstract = {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.}, keywords = {BINDING; ACTIVATION; RESINIFERATOXIN; RESINIFERATOXIN; SENSITIVITY; CAPSAICIN; CAPSAICIN; TRPV1; CALMODULIN; CALMODULIN; Biophysics; Biochemistry & Molecular Biology; TRPV1 CHANNEL; CA2+-DEPENDENT DESENSITIZATION; RECEPTOR TRPV1}, year = {2016}, eissn = {1873-3468}, pages = {2768-2775}, orcid-numbers = {Hetényi, Anasztázia/0000-0001-8080-6992; Wéber, Edit/0000-0002-5904-0619; Szakonyi, Gerda/0000-0002-4366-4283; 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: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} }