The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the alpha methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude. (C) 2017 Elsevier Ltd. All rights reserved.

A comparative study of warheads for design of cysteine protease inhibitors / Silva, Daniel G; Ribeiro, Jean F R; De Vita, Daniela; Cianni, Lorenzo; Franco, Caio Haddad; Freitas-Junior, Lucio H; Moraes, Carolina Borsoi; Rocha, Josmar R; Burtoloso, Antonio C B; Kenny, Peter W; Leitão, Andrei; Montanari, Carlos A. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 27:22(2017), pp. 5031-5035. [10.1016/j.bmcl.2017.10.002]

A comparative study of warheads for design of cysteine protease inhibitors

De Vita, Daniela;Cianni, Lorenzo;
2017

Abstract

The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the alpha methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude. (C) 2017 Elsevier Ltd. All rights reserved.
2017
Aldehyde; Covalent inhibitor; Cysteine protease; Nitrile; Oxime; Warhead; Catalytic Domain; Cathepsin L; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Dipeptides; Drug Design; Kinetics; Nitriles; Structure-Activity Relationship
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A comparative study of warheads for design of cysteine protease inhibitors / Silva, Daniel G; Ribeiro, Jean F R; De Vita, Daniela; Cianni, Lorenzo; Franco, Caio Haddad; Freitas-Junior, Lucio H; Moraes, Carolina Borsoi; Rocha, Josmar R; Burtoloso, Antonio C B; Kenny, Peter W; Leitão, Andrei; Montanari, Carlos A. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 27:22(2017), pp. 5031-5035. [10.1016/j.bmcl.2017.10.002]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1404930
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