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A road map for prioritizing warheads for cysteine targeting covalent inhibitorsÁbrányi-Balogh, Péter ...Targeted covalent inhibitors have become an integral part of a number of therapeutic protocols and are the subject of intense research. The mechanism of action of these compounds involves the ... formation of a covalent bond with protein nucleophiles, mostly cysteines. Given the abundance of cysteines in the proteome, the specificity of the covalent inhibitors is of utmost importance and requires careful optimization of the applied warheads. In most of the cysteine targeting covalent inhibitor programs the design strategy involves incorporating Michael acceptors into a ligand that is already known to bind non-covalently. In contrast, we suggest that the reactive warhead itself should be tailored to the reactivity of the specific cysteine being targeted, and we describe a strategy to achieve this goal. Here, we have extended and systematically explored the available organic chemistry toolbox and characterized a large number of warheads representing different chemistries. We demonstrate that in addition to the common Michael addition, there are other nucleophilic addition, addition-elimination, nucleophilic substitution and oxidation reactions suitable for specific covalent protein modification. Importantly, we reveal that warheads for these chemistries impact the reactivity and specificity of covalent fragments at both protein and proteome levels. By integrating surrogate reactivity and selectivity models and subsequent protein assays, we define a road map to help enable new or largely unexplored covalent chemistries for the optimization of cysteine targeting inhibitors.Source: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 160, Dec. 2018, str. 94-107)Type of material - article, component part ; adult, seriousPublish date - 2018Language - englishCOBISS.SI-ID - 4614001
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https://www.sciencedirect.com/science/article/pii/S0223523418308729?via%3DihubDostop preko računalnikov UL
DOI
Author
Ábrányi-Balogh, Péter |
Petri, László |
Imre, Tímea |
Szijj, Péter |
Scarpino, Andrea |
Hrast, Martina |
Mitrović, Ana |
Pečar Fonović, Urša |
Németh, Kristina |
Barreteau, Hélène |
Roper, David I. |
Horváti, Kata, biokemičarka |
Ferenczy, György G. |
Kos, Janko, 1959- |
Ilaš, Janez |
Gobec, Stanislav, 1970- |
Keserü M., György
Topics
covalent inhibitors |
electrophilic warheads |
GSH reactivity assay |
oligopeptide specificity assay |
MurA |
cathepsin B |
cathepsin X
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Ábrányi-Balogh, Péter | |
Petri, László | |
Imre, Tímea | |
Szijj, Péter | |
Scarpino, Andrea | |
Hrast, Martina | 32036 |
Mitrović, Ana | 36440 |
Pečar Fonović, Urša | 19170 |
Németh, Kristina | |
Barreteau, Hélène | |
Roper, David I. | |
Horváti, Kata, biokemičarka | |
Ferenczy, György G. | |
Kos, Janko, 1959- | 04648 |
Ilaš, Janez | 24400 |
Gobec, Stanislav, 1970- | 15284 |
Keserü M., György |
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