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Synthesis and in-silico modeling of novel bisphenyltetrazole drugs for inactivation of rattlesnake venom components

Ridgway, Harry

Institute for Sustainable Industries and Liveable Cities

Victoria University, Melbourne, Australia AquaMem Consulting, Rodeo, New Mexico USA

Matsoukas, John

NewDrug PC, Patras Science Park, Greece Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada Institute for Health and Sport, Victoria University, Melbourne, Australia

Kelaidonis, Konstantinos

Moore, Graham

NewDrug PC, Patras Science Park, Greece

Snake venoms comprise a pharmacologically-complex cocktail of peptides, phospholipases, metalloproteases, serine proteases and other lesser characterized components. Venom biochemistry is optimized to act synergistically to swiftly immobilize both predator and prey animals. Venom phospholipases and metalloproteases in particular are cytotoxic across a broad range of prey species where they exhibit acute myotoxic, neurotoxic and inflammatory host responses. The secreted phospholipase A2 (sPLA2) family includes 12 members with highly conserved sequences and catalytic motifs, including low molecular weight (13–17 kDa), presence of Ca2+ cofactors for catalytic activity, and histidine/aspartic acid dyads in the catalytic site. Elevated sPLA2 levels in humans are associated with serious clinical conditions, e.g., systemic viral and bacterial infections (including Covid-19), adult respiratory disease syndrome, atherosclerosis, cancer, and multiple organ trauma. Here we report the facile synthesis and in-silico modeling of a novel class of antihypertensive bisphenyltetrazoles known as “Bisartans.” Bisartans are members of the “Sartan” family of drugs currently in wide use around the globe for controlling hypertension and related vascular disorders in cardiac patients. Bisartans are distinguished from all other “monotetrazole” Sartan drugs (e.g., Losartan) by harboring dual anionic bisphenyltetrazole groups connected by a central cationic imidazole ring. Because of their uniquely branched molecular structures, and a net negative charge at physiological pH, Bisartans efficiently coordinate with metal cation cofactors required for catalytic activity of venom metalloproteases and PLA2 neurotoxins. Our computational modeling indicates various Bisartan homologs are promising candidates for inactivation of key rattlesnake venom components, including PLA2 and various metalloproteinases, such as Atrolysin-C from Crotalus atrox. Based on molecular docking studies and molecular dynamics (MD) simulations, we predict stable binding of selected Bisartans in the catalytic domains of rattlesnake venom PLA2, Atrolysin-C and related metalloproteinases.