Identification of Kukoamine A, Zeaxanthin, and Clexane as New Furin Inhibitors

International Journal of Molecular Sciences

Irene Martínez-Martínez¹  Maria Carmen Rodenas¹  David Zaragoza-Huesca¹  Julia Peñas-Martínez¹  Salvador Espín¹  Alfonso Pérez-Garrido²  Josefina María Vegara-Meseguer²  Antonio Jesús Banegas-Luna²  Horacio Pérez-Sánchez²  Carlos Martínez-Cortés² 

[1] Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, CIBERER, Universidad de Murcia, IMIB-Arrixaca, 30003 Murcia, Spain;Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, UCAM Universidad Católica de Murcia, 30107 Guadalupe, Spain;

关键词: furin;    virtual screening;    inhibitors;    CMK;   

DOI  :  10.3390/ijms23052796

来源: DOAJ

【 摘 要 】

The endogenous protease furin is a key protein in many different diseases, such as cancer and infections. For this reason, a wide range of studies has focused on targeting furin from a therapeutic point of view. Our main objective consisted of identifying new compounds that could enlarge the furin inhibitor arsenal; secondarily, we assayed their adjuvant effect in combination with a known furin inhibitor, CMK, which avoids the SARS-CoV-2 S protein cleavage by means of that inhibition. Virtual screening was carried out to identify potential furin inhibitors. The inhibition of physiological and purified recombinant furin by screening selected compounds, Clexane, and these drugs in combination with CMK was assayed in fluorogenic tests by using a specific furin substrate. The effects of the selected inhibitors from virtual screening on cell viability (293T HEK cell line) were assayed by means of flow cytometry. Through virtual screening, Zeaxanthin and Kukoamine A were selected as the main potential furin inhibitors. In fluorogenic assays, these two compounds and Clexane inhibited both physiological and recombinant furin in a dose-dependent way. In addition, these compounds increased physiological furin inhibition by CMK, showing an adjuvant effect. In conclusion, we identified Kukoamine A, Zeaxanthin, and Clexane as new furin inhibitors. In addition, these drugs were able to increase furin inhibition by CMK, so they could also increase its efficiency when avoiding S protein proteolysis, which is essential for SARS-CoV-2 cell infection.

【 授权许可】

Unknown