Heterocyclic electrophiles as new MurA inhibitors

Keeley, Aaron; Ábrányi‐Balogh, Péter; Hrast, Martina; Imre, Tı́mea; Ilaš, Janez; Gobec, Stanislav; Keserü, György M.

doi:10.1002/ardp.201800184

Cited by 26 publications

(42 citation statements)

References 14 publications

(16 reference statements)

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“…One of these free amines provides an immediate growth vector towards the catalytic pocket. The compounds have reasonable stability in water 49 and limited reactivity against GSH (t 1/2 = 2.2 and 52.3 h, respectively), well above suggested reactivity limits 50 . They are also inactive against various covalent targets (HDAC8, MAO-A, MAO-B, MurA) and benchmark proteins.…”

Section: Resultsmentioning

confidence: 74%

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

et al. 2020

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COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

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Section: Resultsmentioning

confidence: 74%

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

et al. 2020

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“…Next, dione 13 was condensed with various amines in the presence of AcOH as catalyst at 65 °C to generate the desired enaminones (14a-e) in moderate yields [18,22]. Bromination of all enaminones In continuation of our interests in finding new MurA inhibitors and in the use of the cyclobutyl motif in drug discovery [6,[15][16][17], here we describe cyclobutenaminone derivatives with carefully-modulated electrophilic character as new warheads for covalently targeting the Cys115 residue in the active site of MurA.…”

Section: Resultsmentioning

confidence: 99%

“…MurA is a preferred antibacterial target, as there is no human orthologue for the enzyme. Known MurA inhibitors contain a three- (1,3), five- (2,(4)(5)(6)(7)(8)(9) or occasionally six-membered (10) heterocycle equipped with a halogen atom leaving group (6,10), or an epoxide ring (1,3) that are prone to nucleophilic substitution. Other inhibitors contain a double bond (2,4,5,(7)(8)(9) that is available for Michael addition (Figure 1) [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Bromo-Cyclobutenaminones as New Covalent UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors

et al. 2020

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Drug discovery programs against the antibacterial target UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and five-membered heterocyclic rings. In the current study, the reactivity of four-membered rings was carefully modulated to obtain a novel family of covalent MurA inhibitors. Screening a small library of cyclobutenone derivatives led to the identification of bromo-cyclobutenaminones as new electrophilic warheads. The electrophilic reactivity and cysteine specificity have been determined in a glutathione (GSH) and an oligopeptide assay, respectively. Investigating the structure-activity relationship for MurA suggests a crucial role for the bromine atom in the ligand. In addition, MS/MS experiments have proven the covalent labelling of MurA at Cys115 and the observed loss of the bromine atom suggests a net nucleophilic substitution as the covalent reaction. This new set of compounds might be considered as a viable chemical starting point for the discovery of new MurA inhibitors.

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“…One of these free amines provides 279 an immediate growth vector towards to catalytic pocket. The compounds have reasonable 280 stability in water(Keeley et al, 2018) and limited reactivity against GSH (t1/2= 2.2 and 52.3 281 h, respectively), well above suggested reactivity limits(Fuller et al, 2016). They are also 282 inactive against various covalent targets (HDAC8, MAO-A, MAO-B, MurA) and benchmark 283 proteins.…”

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confidence: 89%

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Douangamath

Fearon

Gehrtz

et al. 2020

Preprint

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SummaryCOVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments was progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

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Heterocyclic electrophiles as new MurA inhibitors

Cited by 26 publications

References 14 publications

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Bromo-Cyclobutenaminones as New Covalent UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

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