Development and application of novel electrophilic warheads in target identification and drug discovery

Liu, Yue; Lv, Shumin; Peng, Lijie; Xie, Chengliang; Gao, Liqian; Sun, Hongyan; Lin, Ligen; Ding, Ke; Li, Zhengqiu

doi:10.1016/j.bcp.2021.114636

Cited by 24 publications

(21 citation statements)

References 103 publications

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“…The discovery of the target protein is essential to elucidate the medicinal properties of a leading compound. The binding site conformation of the target proteins will provide additional information to design and synthesize the new leading compounds with better safety, higher activity, and better medicinal properties [20,21]. Therefore, we focused on the discovery and identification of the ABG-001 target proteins to do research work in this study.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells

et al. 2021

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Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from gentisides with a remarkable neuritogenic activity. However, the target of ABG-001 is yet to be defined to date. In this study, the potential target of ABG-001 was investigated via an activity-based protein profiling (ABPP) analysis, which is a chemical proteomic method for target identification by using chemical probes. Results indicated that the potential target proteins of ABG-001 were heat shock cognate 70 kDa protein (Hsc70), 78 kDa glucose-regulated protein (GRP78), and 14-3-3 theta protein. Then, the potential target of ABG-001 was confirmed by using inhibitors, the cellular thermal shift assay (CETSA) and small-interfering RNA (siRNA) analysis. The inhibitor of Hsc70 and siRNA significantly decreased the neurite outgrowth induced by ABG-001. Furthermore, ABG-001 induced neurite outgrowth was reduced by siRNA against Hsc70, and the results of CETSA suggested that Hsc70 showed a significant thermal stability-shifted effect upon ABG-001 treatment. These results indicated that Hsc70 is the target protein of ABG-001 in PC12 cells.

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Section: Discussionmentioning

confidence: 99%

Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells

et al. 2021

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“…Similar to carbonyl and α-ketoamide warheads, Michael acceptor groups have also been extensively used in the development of covalent inhibitors for cysteinyl enzymes. − Michael acceptor groups (such as α,β-unsaturated carbonyl, vinyl nitriles, vinyl sulfonamides, etc.) offer potential advantages for target inhibition compared to other warheads; the Michael acceptor groups inhibit the enzymes via conjugate addition of the nucleophilic cysteinyl −SH to the electrophilic Cβ of the unsaturated system, producing a nearly irreversible and longer lasting adduct.…”

Section: Electrophilic Warheads In Covalent Sars-cov-2 Mpro Inhibitionmentioning

confidence: 99%

“…An interesting approach has been provided by the covalent inhibition of the SARS-CoV-2 M PRO cysteinyl protease: − the catalytic sulfur of Cys 145 is covalently trapped by an electrophilic moiety P1′, a reactive warhead that mimics the amide peptide of the viral polyproteins. To be successful in the covalent inhibition, the inhibitors must meet basic structural requirements: a P1 portion, usually a cyclic glutamine analogue, capable of interacting with amino acids such as His 163 , Glu 166 , and His 172 via hydrogen bonds and hydrophobic interactions; P2 and P3 moieties, projected into hydrophobic pockets (S2 and S3/S4) and characterized by substituent groups capable of favorable hydrophobic interactions with the amino acids of these sites (Figure a).…”

Section: Introductionmentioning

confidence: 99%

“…The covalent inhibition strategy has already been pursued against other proteases, including MERS and SARS-CoV-1, with remarkable results . Indeed, compared to traditional noncovalent agents, the electrophilic warhead inhibitors provide better efficacy, higher potency, longer residence time in the binding site of the receptor, sustained pharmacological action, and the ability to overcome resistance. − …”

Section: Introductionmentioning

confidence: 99%

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Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

et al. 2022

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The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine 145 of SARS-CoV-2 M PRO with selective antiviral drugs will arrest the replication process of the virus without affecting human catalytic pathways. In this Perspective, we analyzed the in silico, in vitro, and in vivo data of the most representative examples of covalent SARS-CoV-2 M PRO inhibitors reported in the literature to date. In particular, the studied molecules were classified into eight different categories according to their reactive electrophilic warheads, highlighting the differences between their reversible/irreversible mechanism of inhibition. Furthermore, the analyses of the most recurrent pharmacophoric moieties and stereochemistry of chiral carbons were reported. The analyses of noncovalent and covalent in silico protocols, provided in this Perspective, would be useful for the scientific community to discover new and more efficient covalent SARS-CoV-2 M PRO inhibitors.

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“…To overcome this limitation, many novel electrophilic warheads such as 2-sulfonylpyridine, bicyclo[1.1.0]butane (BCB) carboxylic amide, cyanamide, sulfonyl fluoride, oxaziridine, sulfur-triazole, sulfotetrafluorophenyl (STP) ester, α-chlorofluoroacetamide, alkynyl benzoxazine, vinylheteroarene, vinyl/alkynyl pyridine, and cyclopropene/cyclopropenone , that target tyrosine, methionine, lysine, and cysteine residues have been developed in recent years. These electrophiles have already been employed in activity-based protein profiling for the discovery of new druggable targets and development of novel covalent inhibitors with excellent pharmaceutical properties …”

Section: Introductionmentioning

confidence: 99%

Ynamide Electrophile for the Profiling of Ligandable Carboxyl Residues in Live Cells and the Development of New Covalent Inhibitors

Zhang

et al. 2022

J. Med. Chem.

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Covalent inhibitors with an electrophilic warhead have received considerable attention due to their remarkable pharmacological properties. However, the electrophilic warhead in covalent drugs is often an α, β-unsaturated amide, and the targets are mainly cysteine or lysine residues. Thus, the development of novel electrophiles that can target other amino acids is highly desirable. Ynamide, a useful and versatile building block, is commonly employed in the construction of various compounds in organic synthesis. The performance of this functional group in a proteome-wide environment has been studied here for the first time, and it has been shown that it can efficiently modify carboxyl residues in situ and in vitro. Upon incorporation of this ynamide warhead into the pharmacophores of kinase inhibitors, the resulting compound showed moderate inhibition against the EGFR L858R mutant but not against EGFR WT. This novel electrophilic group can be used in the development of new types of covalent inhibitors.

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Development and application of novel electrophilic warheads in target identification and drug discovery

Cited by 24 publications

References 103 publications

Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells

Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

Ynamide Electrophile for the Profiling of Ligandable Carboxyl Residues in Live Cells and the Development of New Covalent Inhibitors

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