dianas 9 (1) Carrasco-Rubio etal 2020 Theoretical study to find a novel drug inhibitor of SFRP1 as a new treatment for Alzheimer’s disease

SECUAH 2021

dianas | Vol 9 No 1 | marzo 2020 | e202003

Theoretical study to find a novel drug inhibitor of SFRP1 as a new treatment for Alzheimer's disease

Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá (UAH). Alcalá de Henares (Madrid)

lauralcr20@hotmail.com

V Congreso de Señalización Celular, SECUAH 2020.
16-18 de marzo, 2020. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by progressive neuronal death that mainly affects cortical regions of the brain and part of the limbic system. Alterations are produced in memory, language, perception, orientation and executive functions, being one of the main causes of dementia in the world. One of the main characteristics of AD is the appearance of senile or amyloid plaques. Senile plaques are extraneural deposits formed by the accumulation of the Aβ-42 peptide (β-amyloid peptide), produced by the proteolysis of amyloid precursor protein (APP) by β-secretase and γ-secretase. In contrast, non-pathological cleavage of APP occurs by α-secretasa and γ-secretasa. AD is expected to affect more than 150 million people by 2050, becoming a serious socioeconomic problem. Despite all efforts, no effective therapy has been achieved yet. Due to inefficiencies in therapies against currently known therapeutic targets, in the present work we have investigated the SFRP1 protein as a new potential therapeutic target. SFRP1 is overexpressed in patients with AD producing inhibition of ADAM10 (α-secretasa), promoting the formation of the β-amyloid peptide. We have developed, in a theoretical way, a project to obtain compounds that inhibit SFRP1 and prevent its union to ADAM10, so that α-secretase can perform its function. For this theoretical project, we assume that we have a library with numerous chemical compounds from which we design a drug discovery process with the aim of achieving a compound with the capacity to inhibit SFRP1 whose properties allow its use as a drug. For this purpose, we have developed a computational pre-screening and a subsequent High Throughput Screening (HTS) using FRET. This trial would allow us to identify which compounds have a higher percentage of inhibition and would be reevaluated with HTS to select those with lower IC-50 and higher selectivity against SFRP1. Compounds with the ability to cross the blood-brain barrier will be evaluated by PAMPA assay, in vivo studies will be performed on telencephalic cells and in vitro studies will be performed on AD murine models to confirm their efficacy. Finally, preclinical pharmacology and toxicology studies of the selected compounds would be developed as a previous step to the study of the drug in clinical trials to check whether it could finally be used as a treatment for AD.

Citation: Carrasco-Rubio L, González-Carrion E, Martínez-del-Río J, Martínez-Pasabados I (2020) Theoretical study to find a novel drug inhibitor of SFRP1 as a new treatment for Alzheimer's disease. Proceedings of the V Congreso de Señalización Celular, SECUAH 2020. 16-18 de marzo, 2020. Universidad de Alcalá. Alcalá de Henares, Madrid. España. dianas 9 (1): e202003. ISSN 1886-8746 (electronic) journal.dianas.e202003. URI http://hdl.handle.net/10017/15181

Copyright: ©2020 Carrasco-Rubio L, González-Carrion E, Martínez-del-Río J, Martínez-Pasabados I. Algunos derechos reservados. This is an open-access work licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. http://creativecommons.org/licenses/by-nc-nd/4.0/

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