A road map for prioritizing warheads for cysteine targeting covalent inhibitors

Ábrányi‐Balogh, Péter; Petri, László; Imre, Tı́mea; Szijj, Péter A.; Scarpino, Andrea; Hrast, Martina; Mitrović, Ana; Fonović, Urša Pečar; Németh, Krisztina; Barreteau, Hélène; Roper, David I.; Horváti, Kata; Ferenczy, György G.; Kos, Janko; Ilaš, Janez; Gobec, Stanislav; Keserü, György M.

doi:10.1016/j.ejmech.2018.10.010

Cited by 84 publications

(87 citation statements)

References 53 publications

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“…The selectivity of 44 toward nucleophilic residues was further investigated with an oligopeptide KGDYHFPIC. This nonapeptide (NP) is designed to harbor an array of nucleophilic residues, i.e., cysteine, lysine, tyrosine, aspartate and histidine [25]. Analysis by LC-MS/MS can identify the binding to a particular residue from fragmentation patterns.…”

Section: Covalent Binding To Glutathione and Nonapeptidementioning

confidence: 99%

“…Analysis of NP (KGDYHFPIC) incubated (16 h, rt) with 44 or 42 was performed according to Ábrányi-Balogh et al [25].…”

Section: Nonapeptide Assaymentioning

confidence: 99%

“…Other residues have been targeted as well with various warheads, i.e., lysine with activated ester [16] or arylsulfonyl fluoride [20], tyrosine with an arylsulfonyl fluoride [22], or asparagine with an aziridinium ion [17]. Indeed, recent extensions of the diversity in warheads give an opportunity for the fine-tuning of the reactivity [24,25].…”

Section: Introductionmentioning

confidence: 99%

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Covalent Inhibition of the Histamine H3 Receptor

et al. 2019

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Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H 3 receptor (H 3 R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H 3 R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H 3 R was validated with washout experiments and leads to inverse agonism on H 3 R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H 3 R conformation and to study the consequences of prolonged inhibition of the H 3 R.

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Section: Covalent Binding To Glutathione and Nonapeptidementioning

confidence: 99%

“…Analysis of NP (KGDYHFPIC) incubated (16 h, rt) with 44 or 42 was performed according to Ábrányi-Balogh et al [25].…”

Section: Nonapeptide Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Covalent Inhibition of the Histamine H3 Receptor

et al. 2019

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“…The CPs are effectively modulated by several classes of covalent inhibitors (CI) due to the presence of the active Cys residue of the enzyme, which facilitates nucleophilic attack to a susceptible electrophile. Examples of successful drugs that act through a covalent mechanism are aspirin and omeprazole (ÁBRÁNYI-BALOGH et al, 2018;SINGH et al, 2011).…”

Section: Covalent Reversible Inhibitorsmentioning

confidence: 99%

“…can be translated into lower and less frequent dosing with decreased potential for off-target effects. Covalent drugs also result in long residence times on the target, which can lead to prolonged action (ÁBRÁNYI-BALOGH et al, 2018;DE CESCO et al, 2017;SMITH et al, 2009).…”

Section: Possesses Many Advantages Over Non-covalent Compounds Sumentioning

confidence: 99%