Peptidomimetic’s

Pioneering group in Spain in the field of peptidomimetics, a concept that encompasses small non-peptidic molecules capable of mimicking or blocking the physiological functions of peptides and proteins. This type of compounds aims to solve the pharmacokinetic limitations of peptides/proteins for their therapeutic application. Research in this field requires the coordinated use of molecular modeling techniques, various synthetic methodologies, both in solution and solid phase (peptides and small molecules), and the corresponding biological evaluation. The group has experience in the preparation of enzyme inhibitors, mimetics of analgesic and antitumor peptides, neuropeptides, and modulators of protein-protein and ion channel interactions. In the search for new analgesic, antitumor, cardiovascular and neuroprotective agents, in recent years the activity of the group is been focused on two medicinal chemistry sub-lines, dedicated to get and optimize new chemical entities for specific therapeutic applications, and a transversal sub-line, framed in biological chemistry, for the development of new tools of general utility in the field.

1-Inhibition/stabilization of protein-protein interactions. Mainly involved in the development of neurodegenerative (DREAM/ATF6) and cardiovascular (MR-coactivators) processes.

2- Modulation of ion channels and associated proteins. We are working on TRP and nACh channels, involved in inflammatory and neuropathic pain, as well as on the DREAM/Kv4.3 interaction for neurodegenerative disorders, and on the search for non-steroidal antagonists of MR for cardiovascular diseases.

3- General methodologies for peptidomimetics. Including molecular modeling, virtual screening, fluorescent probes for biosensors and secondary structure mimetics.

The collaboration with companies in the pharmaceutical sector (Antibiotics, SA, Dr. Andreu SA, Deretil SA, Pharma Mar SA, Janssen Cilag S.A., Givaudan AG.) and the multidisciplinary training of young researchers are two constants in the group. At present, people trained in the peptidomimetic’s group occupy permanent and highly qualified positions in national and international academic centers and in diverse pharmaceutical companies.

RESEARCH LINES

Antivirals against SARS-CoV-2

Screening of group collections
Rational design

General Methodologies

Mimetics of Peptide Secondary Structure
Computer Aided Drug Design
Molecular Diversity Generation
Fluorescence Biosensors

Protein-Protein Interactions

Modulators of the Calcium Neuronal Sensor DREAM
Modulators of the Mineralocorticoid Receptor (MR)

Ionic Channels and Associated Proteins

Modulators of TRP and Kv4 Channels
Allosteric Modulators of Nicotinic Channels
Ortosteric Antagonists of MR

SELECTED PUBLICATIONS (last 5 years)

Evolution in non-peptide α–helix mimetics on the road to effective protein-protein interaction modulators.

Algar, S.; Martín-Martínez, M.; González-Muñiz, R.

Eur. J. Med. Chem. 2021, 211, 113015; https://doi.org/10.1016/j.ejmech.2020.113015.

Phenylalanine-derived β-Lactam TRPM8 modulators. Configuration effect on the antagonist activity

Bonache, M.A.; Llabrés, P.J.; Martín-Escura, C.; De la Torre-Martínez, R.; Medina-Peris, A.; Gómez-Monterrey, I.; Roa, A.M.; Fernández-Ballester, G.; Ferrer-Montiel, A.; Fernández-Carvajal, A.; González-Muñíz, R.

Int. J. Mol. Sci., 2021, 22, 3390; https://doi.org/10.3390/ijms22052370.

Pharmacological Approaches for the Modulation of the Potassium Channel Kv4.x and KChIPs.

Cercós, D. A. Peraza, A.Benito-Bueno, P. G. Socuéllamos, A. Aziz-Nignan, D. Arrechaga-Estévez, E. Beato, E. Peña-Acevedo, A. Albert, J. A. González-Vera, Y. Rodríguez, M. Martín-Martínez, C. Valenzuela and M. Gutiérrez-Rodríguez

Int. J. Mol. Sci. 2021, 22(3), 1419; https://doi.org/10.3390/ijms22031419.

Natural Polyhydroxy Flavonoids, Curcuminoids and Synthetic Curcumin Analogs, as α7 nAChRs Positive Allosteric Modulators.

Ximenis, M.; Mulet, J.; Sala, S.; Sala, F.; Criado, M.; González-Muñíz, R. Pérez de Vega, M.J.

Int. J.Mol. Sci., 2021, 22, 973. https:// doi.org/10.3390/ijms22020973.

Investigational drugs in early phase clinical trials targeting thermoTRP channels.

Fernández-Carvajal, A.; González-Muñiz, R.; Fernádez-Ballester, G.; Ferrer-Montiel, A.

Expert Opin. Inv. Drugs 2020, 29, 1209–1222; https://doi.org/10.1080/13543784.2020.1825680.

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity.

LLabrés, P.J.; Bonache, M.A.; Martín-Escura, C.; De la Torre-Martínez, R.; Fernández-Carvajal, A.; Fernández-Ballester, G.; Ferrer-Montiel, A.; González-Muñiz, R. Sci. Rep. 2020, 10, 14154.

Characterization of Novel Synthetic Polyphenols: Validation of Antioxidant and Vasculoprotective Activities.

Pérez de Vega, M.J. Moreno-Fernádez, S.; Pontes-Quero, G.M.; González-Amor, M.; Vázquez-Lasa, B.; Sabater-Muñoz, B.; Briones, A.M.; Aguilar, M.R.; Miguel, M.; González-Muñiz, R. Antioxidants 2020, 9(9), 787.

Smart lanthanide antennas for sensing water.

Fueyo-Gonzalez, F.; Garcia-Fernandez, E.; Martinez, D.; Infantes, L.; Orte, A.; Gonzalez-Vera, J. A.; Herranz, R. Chem. Commun. 2020, 56(41), 5484-5487.

Recent Progress in TRPM8 modulation: An update.

González-Muñiz, R., Bonache, M.A.; Martín-Escura, C.; Gómez Monterrey, I. Int. J. Mol. Sci. 2019, 20, E2618.

1-(2’,5’-Dihydroxyphenyl)-3-(2-fluoro-4-methoxyphenyl)-1-propanone: A positive allosteric modulator of a7 nicotinic receptors with analgesic and neuroprotective activity.

Pérez de Vega, M.J.; Fernandez Mendivil, C.; de la Torre Martínez, R.; González-Rodríguez,S.; Mullet, J.; Sala, F.; Sala, S.;Criado, M.; Moreno-Fernández, S.; Miguel, M.; Fernández-Carvajal, A.; Ferrer-Montiel, A.; García López, M.; González-Muñiz, R. ACS Chem. Neurochem. 2019, 10 (8), 3900-3909.

Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington’s disease treatment.

Lopez-Hurtado, A.; Peraza, D.A.; Cercos, P.; Lagartera, L..; Gonzalez, P; Dopazo, X.M.; Herranz R.; Gonzalez, T.; Martin-Martinez,, M;. Mellström B;. Naranjo, J.R.; Valenzuela, C.; Gutierrez-Rodriguez ,M.

Sci. Rep. 2019 , 9, 7260. DOI: 10.1038/s41598-019-43677-7.

Identification of IQM-266, a novel DREAM ligand that modulates K_V4 currents D.A. Peraza, P. Cercós, P. Miaja, Y. G. Merinero, L. Lagartera, P. G. Socuéllamos, C. Izquierdo García, S. A. Sánchez, A. López-Hurtado, M. Martín-Martínez, L. A. Olivos-Oré, J. R. Naranjo, A. R. Artalejo, M. Gutiérrez-Rodríguez and C. Valenzuela.

Front. Mol. Neurosci. 2019, 12, 11. DOI: 10.3389/fnmol.2019.00011

Small library of triazolyl polyphenols correlating antioxidant activity and stability with the number and position of hydroxyl groups M.A. Bonache, S. Moreno-Fernández, M. Miguel, B. Sabater-Muñoz, R. González-Muñiz

ACS Comb. Sci. 2018, 20, 694-699. DOI: 10.1021/acscombsci.8b00118

Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of α7 nicotinic receptors with analgesic activity Balsera, J. Mulet, S. Sala, F Sala, R de la Torre, S. González-Rodríguez, A. Plata, L. Naesens, A. Fernández-Carvajal, A. Ferrer-Montiel, M. Criado, M. J. Pérez de Vega, R. González-Muñiz

Eur. J. Med. Chem. 2018, 143, 157-165. DOI: 10.1016/j.ejmech.2017.10.083

Synthesis, high-throughput screening and pharmacological characterization of β–lactam derivatives as TRPM8 antagonists R. de la Torre-Martínez, M. Angeles Bonache, P. J. Llabrés-Campaner, B. Balsera, A. Fernández-Carvajal, G. Fernández-Ballester, A. Ferrer-Montiel, M. J. Pérez de Vega, R. González-Muñiz

Sci. Rep. 2017, 7: 10766. DOI: 10.1038/s41598-017-10913-x

Modulating mineralocorticoid receptor with non-steroid antagonists. New opportunities for the development of potent and selective LBD ligands without off-target side-effects. M. Martín Martínez, F. Gordillo, D. Álvarez de la Rosa, Y. Rodríguez, G. Gerona Navarro, R. González Muñiz, M.-M. Zhou

Med. Chem. (Perspective) 2017, 60, 2629-2650.

DOI: 10.1021/acs.jmedchem.6b01065

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer M.J. Pérez de Vega, I. Gómez-Monterrey, A. Ferrer-Montiel, R. González-Muñiz

Med. Chem. (Perspective) 2016, 59(22), 10006-10029.

DOI: 10.1021/acs.jmedchem.6b00305

1,3-Diphenylpropan-1-ones as Allosteric Modulators of α7 nACh Receptors with Analgesic and Antioxidant Properties M. Criado*, B. Balsera, J. Mulet, S. Sala, F. Sala, R. de la Torre-Martínez, A. Fernández-Carvajal, A. Ferrer-Montiel, S. Moreno-Fernández, M. Miguel, M. J. Pérez de Vega, R. González-Muñiz.

Future Med. Chem. 2016, 8, 731-749. DOI: 10.4155/fmc-2015-0001

Highly solvatochromic and tunable fluorophores based on a 4,5-quinolimide scaffold: novel CDK5 probes. J.A. Gonzalez-Vera, F. Fueyo-Gonzalez, I. Alkorta, M. Peyressatre, M. C Morris, R. Herranz.

Chem. Comm. 2016, 52, 9652-9655. DOI: 10.1039/c6cc04566a

Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease. J.R. Naranjo, H. Zhang, D. Villar, P. González, X.M. Dopazo, J. Morón-Oset, E. Higueras, J.C. Oliveros, M.D. Arrabal, A. Prieto, P. Cercós, T. González, A. De la Cruz, J. Casado-Vela, A. Rábano, C. Valenzuela, M. Gutierrez-Rodriguez, J. Y. Li, B. Mellström.

Clin. Invest. 2016,126, 627-638. DOI: 10.1172/JCI82670.

Experimental and Theoretical Studies on the Rearrangement of 2- Oxoazepane α,α-Amino Acids into 2’-Oxopiperidine β^2,3,3-Amino Acids: An Example of Intramolecular Catalysis D. Núñez-Villanueva, M.A. Bonache L. Lozano, L. Infantes, J. Elguero, I. Alkorta, M.T. García-López,R. González-Muñiz, M. Martín-Martínez

Chemisty: A Eur. J. 2015, 21, 2489-2500. DOI: 10.1002/chem.201405640

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