{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T19:16:48Z","timestamp":1789759008367,"version":"4.0.1"},"reference-count":73,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin \u2018antipeptides\u2019. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor \u2018switching\u2019 between an activated state invoking receptor dimerization\/G protein coupling and an inverse agonist state mediated by an alternative\/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His\/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans (\u2018Bisartans\u2019) to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1\u20137). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells.<\/jats:p>","DOI":"10.3390\/molecules27154854","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T04:04:00Z","timestamp":1659326640000},"page":"4854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Actions of Novel Angiotensin Receptor Blocking Drugs, Bisartans, Relevant for COVID-19 Therapy: Biased Agonism at Angiotensin Receptors and the Beneficial Effects of Neprilysin in the Renin Angiotensin System"],"prefix":"10.3390","volume":"27","author":[{"given":"Graham J.","family":"Moore","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada"},{"name":"Pepmetics Inc., 772 Murphy Place, Victoria, BC V8Y 3H4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Ridgway","sequence":"additional","affiliation":[{"name":"Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne, VIC 8001, Australia"},{"name":"AquaMem Consultants, Rodeo, New Mexico, NM 88056, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Kelaidonis","sequence":"additional","affiliation":[{"name":"NewDrug PC, Patras Science Park, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8728-6245","authenticated-orcid":false,"given":"Christos T.","family":"Chasapis","sequence":"additional","affiliation":[{"name":"NMR Facility, Instrumental Analysis Laboratory, School of Natural Sciences, University of Patras, 26504 Patras, Greece"},{"name":"Institute of Chemical Engineering Sciences, Foundation for Research and Technology, Hellas (FORTH\/ICE-HT), 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Ligielli","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National and Kapodistrian University of Athens, 15784 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5309-992X","authenticated-orcid":false,"given":"Thomas","family":"Mavromoustakos","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National and Kapodistrian University of Athens, 15784 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9190-6913","authenticated-orcid":false,"given":"Joanna","family":"Bojarska","sequence":"additional","affiliation":[{"name":"Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5554-2964","authenticated-orcid":false,"given":"John M.","family":"Matsoukas","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada"},{"name":"NewDrug PC, Patras Science Park, 26504 Patras, Greece"},{"name":"Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1161\/01.RES.9.3.762","article-title":"Angiotensin, the Renal Pressor Hormone","volume":"9","author":"Bumpus","year":"1961","journal-title":"Circ. 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