Protein-Protein Interaction Modulators

The group’s activity focuses on the search for Protein-Protein Interaction (PPI) Modulators with biomedical applications. Understanding the biological processes whose dysregulation leads to pathological conditions is essential for the development of new drugs. Protein-protein interactions (PPIs) play a key role in most cellular processes and represent a highly interesting group of targets for the development of new therapies.

The complete map of protein-protein interactions is known as the interactome, and when ion channels are involved, it is referred to as the channelosome. Knowledge of these networks will help elucidate the molecular basis of diseases and facilitate the identification of new biological targets of therapeutic interest. It will also serve as a foundation for the development of specific drugs.

Despite significant advances in scientific understanding of the human interactome and its relationship with various diseases, there are still many protein-protein interactions to be identified and their roles in disease pathophysiology to be unraveled.

Among the tools that can contribute to a better understanding of PPIs are the development of small molecules capable of binding to specific proteins and modulating their interactions, laying the groundwork for innovative drugs with novel
mechanisms of action. Additionally, the development of new fluorophores to visualize these interactions is also a valuable approach.

Research lines

Development of molecular tools to explore alternative therapeutic pathways for cardiovascular diseases.

Identification of preclinical candidates with novel mechanisms of action to advance the development of direct-acting antivirals.

Design, synthesis, and photophysical characterization of new fluorophores for bioimaging.

Working closely with national and international experts in electrophysiology, virology, molecular modeling, pharmacology, and photophysics to drive innovative research and support the training of young scientists developing their careers within our team.

Financed Projects

State Program for Research and Experimental Development:

*PID2022-137214OB-C22: Role of K_V1.5 y K_V4.3 in atrial fibrillation. Search of new therapeutic targets and molecular tools. IP: Marta Gutiérrez Rodríguez. (01/09/2024-31/08/2027). Funding entity: MICIU/AEI/ 10.13039/501100011033 and by FEDER/UE

*PID2019-104366RB-C22. New molecular tools to unravel the K_V1.5 and K_V4.3 channelosomes involved in atrial fibrillation. IP: Marta Gutiérrez Rodríguez. (01/06/2020-31/12/2023). Funding entity: MCIN/ AEI /10.13039/501100011033

European Union.

*New AntiVirals for Infections with Pandemic Potential. (NAVIPP). Public-private consortium of 12 groups from different European institutions and GlaxoSmithKline. 01/2024-12/2028. IP IQM-CSIC:Marta Gutiérrez-Rodríguez. Funding entity: HORIZON-HLTH-2023-DISEASE-03. (Tackling diseases Call).Proposal number: 101137506

UNESPA:

*Project PIE-CSIC-202380E148 “Development of direct-acting antivirals against coronaviruses – Medicinal Chemistry”. IP: Marta Gutiérrez Rodríguez. (01/09/2023-31/08/2026)

Selected publications

1) Ruiz-Arias, A.; Fueyo-González, F.; Izquierdo-García, C.; Navarro, A.; Gutiérrez-Rodríguez, M.; Herranz, R.; Burgio, C.; Reinoso, A.; Cuerva, J.M.; Orte, A.*; González-Vera, J.A*. Exchangeable Self-Assembled Lanthanide Antennas for PLIM Microscopy. Angew Chem Int Ed Engl. 63, e202314595. (2024) doi: 10.1002/anie.202314595

2) Cruz, F. M.; Macías, A.; Moreno-Manuel, A.; Gutiérrez, I. L. K.; Linarejos Vera-Pedrosa, M.; Martínez-Carrascoso, I.; Sánchez Pérez, P.; Ruiz Robles, J. M.; Bermúdez-Jiménez, F. J.; Díaz-Agustín, A.; Martínez de Benito, F.; Arias-Santiago, S.; Braza-Boils, A.; Martín-Martínez, M.; Gutierrez-Rodríguez, M.; Bernal, J. A.; Zorio, E.; Jiménez-Jaimez, J.; Jalife, J. *. Extracellular Kir2.1C122Y Mutant Upsets Kir2.1- PIP2 Bonds and Is Arrhythmogenic in AndersenTawil Syndrome. Circ. Res. 134. (2024) DOI: 10.1161/CIRCRESAHA.123.323895.

3) Navarro, A.; Ruiz-Arias, A.; Fueyo-González, F.; Izquierdo-García, C.; Peña-Ruiz, T.; Gutiérrez-Rodríguez, M.; Herranz, R.; Cuerva, J.M.; González-Vera, J.A*; Orte, A.*. Multiple pathways for lanthanide sensitization in self-assembled aqueous complexes. Spectrochim Acta A Mol. Biomo.l Spectrosc. 323:124926. (2024) doi: 10.1016/j.saa.2024.124926.

4) Bartolomé-Nebreda, J.M.; de Pascual-Teresa, B.; Gutiérrez-Rodríguez, M.; Martín-Martínez, M. The Spanish Society of Medicinal Chemistry: Promoting Pharmaceutical R&D in Spain since 1977. ChemMedChem. 19(23):e202400511. (2024) doi: 10.1002/cmdc.202400511.

5) Fernández-Varas, B.; Manguan-García, C.; Rodriguez-Centeno, J.; Mendoza-Lupiáñez, L.; Calatayud, J.; Perona, R.; Martín-Martínez, M.; Gutierrez-Rodriguez, M.; Benítez-Buelga, C.; Sastre, L. Hum. Mol. Genet. 33(9):818-834. (2024) doi: 10.1093/hmg/ddae015

6) De Benito-Bueno, A.; Socuellamos, P. G; Merinero, Y. G. and col. M. Gutierrez-Rodriguez *; C. Valenzuela*. Modulation of KV4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2. Int. J. Mol. Sci. 23, 9170 (2022) doi: 10.3390/ijms23169170

7) Socuéllamos, P.G.; Olivos-Oré, L.A.; Barahona, M.V. and col. Gutiérrez-Rodríguez, M.*; Artalejo, A.R.* IQM-PC332, a Novel DREAM Ligand with Antinociceptive Effect on Peripheral Nerve Injury-Induced Pain. Int. J. Mol. Sci., 23, 2142. (2022) doi: 10.3390/ijms23042142

8) Jimenez-Aleman, G. H.; Castro, V.; Londaitsbehere, A.; Gutierrez-Rodriguez, M.; Garaigorta, U.; Solano, R.* and Gastaminza, P.*. SARS-CoV-2 Fears Green: The Chlorophyll Catabolite Pheophorbide A Is a Potent Antiviral. Pharmaceuticals 14, 1048 – 14067 (2021) doi: 10.3390/ph14101048.

9) Cercós, P.; Peraza, D.A.; Benito-Bueno, A.D.; and col. Gutiérrez-Rodríguez, M*. Pharmacological Approaches for the Modulation of the Potassium Channel Kv4.x and KChIPs. Int. J. Mol. Sci., 22, 1419 (2021) doi: 10.3390/ijms22031419

10) Lopez-Hurtado, A.1; Peraza, D. A.1; Cercós, P.1; Lagartera, L.; Gonzalez, P.; Dopazo, X.M.; Herranz, R.; Gonzalez, T.; Martin-Martinez, M.; Mellström, B.; Naranjo, J.R. (AC); Valenzuela, C. (AC); Gutierrez-Rodriguez, M*. Targeting the Downstream Regulatory Element Antagonist Modulator (DREAM) with small-molecules for the treatment of Huntington’s disease. Sci. Rep. 13;9(1):7260 (2019) doi: 10.1038/s41598-019-43677-7

11) Peraza Diego, A.; Cercós P., Miaja P.O, and col. Gutiérrez-Rodríguez M.*, Valenzuela C.* Identification of IQM-266 as a new activator of KV4 currents mediated by the accessory protein DREAM. Front. Mol. Neurosci. 12:11 (2019) doi: 10.3389/fnmol.2019.00011

12) Naranjo, J.R.; Zhang, H.; Villar, D.; González, P.; Dopazo, X.M.; Morón-Oset, J.; Higueras, E.; Oliveros, J.C.; Arrabal, M.D.; Prieto, A.; Cercós, P.; González, T.; De la Cruz, A.; Casado-Vela, J.; Rábano, A.; Valenzuela, C.; Gutierrez-Rodriguez, M.; Li, J.Y.; Mellström, B.* Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease. J. Clin. Inv. 126, 627-638 (2016). Reseñado en Nature Reviews Drug Discovery; 15:169; 2016. doi: 10.1172/JCI82670

PERSONAL