Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics
Δημιουργός/Συγγραφέας:	Kelaidonis, Konstantinos Ligielli, Irene Letsios, Spiros Vidali, Veroniki P Mavromoustakos, Thomas Vassilaki, Niki Moore, Graham J Hoffmann, Weronika Węgrzyn, Katarzyna Ridgway, Harry [EL] Χασάπης, Χρήστος[EN] Chasapis, Christos Matsoukas, John M
Ημερομηνία:	2023-05-08
Γλώσσα:	Αγγλικά
ISSN:	1422-0067
DOI:	10.3390/ijms24098454
Άλλο:	37176159
Περίληψη:	This study is an extension of current research into a novel class of synthetic antihypertensive drugs referred to as "bisartans", which are bis-alkylated imidazole derivatives bearing two symmetric anionic biphenyltetrazoles. Research to date indicates that bisartans are superior to commercially available hypertension drugs, since the former undergo stronger docking to angiotensin-converting enzyme 2 (ACE2). ACE2 is the key receptor involved in SARS-CoV-2 entry, thus initiating COVID-19 infection and in regulating levels of vasoactive peptides such as angiotensin II and beneficial heptapeptides A(1-7) and Alamandine in the renin-angiotensin system (RAS). In previous studies using in vivo rabbit-iliac arterial models, we showed that Na+ or K+ salts of selected Bisartans initiate a potent dose-response inhibition of vasoconstriction. Furthermore, computational studies revealed that bisartans undergo stable binding to the vital interfacial region between ACE2 and the SARS-CoV-2 "receptor binding domain" (i.e., the viral RBD). Thus, bisartan homologs are expected to interfere with SARS-CoV-2 infection and/or suppress disease expression in humans. The primary goal of this study was to investigate the role of tetrazole in binding and the network of amino acids of SARS-CoV-2 Spike RBD-ACE2 complex involved in interactions with sartans. This study would, furthermore, allow the expansion of the synthetic space to create a diverse suite of new bisartans in conjunction with detailed computational and in vitro antiviral studies. A critical role for tetrazole was uncovered in this study, shedding light on the vital importance of this group in the binding of sartans and bisartans to the ACE2/Spike complex. The in silico data predicting an interaction of tetrazole-containing sartans with ACE2 were experimentally validated by the results of surface plasmon resonance (SPR) analyses performed with a recombinant human ACE2 protein.
Τίτλος πηγής δημοσίευσης:	International journal of molecular sciences
Τόμος/Κεφάλαιο:	24
Τεύχος:	9
Θεματική Κατηγορία:	[EL] Βιοχημεία[EN] Biochemistry [EL] Χημική μηχανική[EN] Chemical engineering [EL] Δομική Βιολογία[EN] Structural Biology [EL] Βιοπληροφορική[EN] Bioinformatics
Λέξεις-Κλειδιά:	SARS-CoV-2 COVID-19 Bisartans Tetrazole ACE2 RAS RBD
EU Grant:	Research Seed Grant from National Hellenic Research Foundation (NHRF) Special Account for Research Grants (SARG), National Kapodistrian University of Athens (NKUA)
Κάτοχος πνευματικών δικαιωμάτων:	© 2023 by the authors. Licensee MDPI, Basel, Switzerland.
Όροι και προϋποθέσεις δικαιωμάτων:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://www.mdpi.com/1422-0067/24/9/8454
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο