Propargyl Amides as Irreversible Inhibitors of Cysteine Proteases—A Lesson on the Biological Reactivity of Alkynes

Arkona, Christoph; Rademann, Jörg

doi:10.1002/anie.201303544

Cited by 23 publications

(23 citation statements)

References 16 publications

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“…Work by Sommer et al revealed that the catalytic triad does not have to be intact for covalent bond formation, indicating a proximity-driven reactivity. 22 Although it was believed that the reactivity of the alkyne resulted from a template effect: recognition of (large) protein fragments driving the formation of the thermodynamically unfavored Markovnikov-type thiovinyl product, 23 here we show that strong enough binding can be achieved with a small molecule recognition part. This study highlights the potential of alkynes as latent electrophiles in irreversible covalent small molecule inhibitors, as demonstrated for cathepsin K (CatK).…”

Section: Introductionmentioning

confidence: 57%

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

et al. 2019

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Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation ( k inact ) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.

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Section: Introductionmentioning

confidence: 57%

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

et al. 2019

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“…The bioorthogonality of terminal alkynes has recently been questioned due to the observed covalent modification of cysteines by propargyl amides [47,48,49 ]. Ubiquitin propargylated at the C-terminus (Ub-Prg) inhibits a number of deubiquitinating enzymes (DUBs) through covalent modification of the active-site cysteine nucleophile [47] (Figure 2h).…”

Section: Current Opinion In Chemical Biologymentioning

confidence: 98%

Covalent protein modification: the current landscape of residue-specific electrophiles

Shannon

Weerapana

2015

Current Opinion in Chemical Biology

198

178

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“…They reported the high specificity of the reaction, and deduced that it was driven by the close proximity and alignment of the alkyne and the thiolate ion in the enzyme oxoanion hole, hence driving the reaction forward. This remarkable discovery of irreversible inhibition of cysteine proteases in such a selective manner might find use in activity‐based protein probes, potentially for many protease–substrate partners …”

Section: Thiol‐ene and Thiol‐yne Reactionsmentioning

confidence: 99%

Chemical Protein Modification through Cysteine

2016

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The modification of proteins with non-protein entities is important for a wealth of applications, and methods for chemically modifying proteins attract considerable attention. Generally, modification is desired at a single site to maintain homogeneity and to minimise loss of function. Though protein modification can be achieved by targeting some natural amino acid side chains, this often leads to ill-defined and randomly modified proteins. Amongst the natural amino acids, cysteine combines advantageous properties contributing to its suitability for site-selective modification, including a unique nucleophilicity, and a low natural abundance--both allowing chemo- and regioselectivity. Native cysteine residues can be targeted, or Cys can be introduced at a desired site in a protein by means of reliable genetic engineering techniques. This review on chemical protein modification through cysteine should appeal to those interested in modifying proteins for a range of applications.

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Propargyl Amides as Irreversible Inhibitors of Cysteine Proteases—A Lesson on the Biological Reactivity of Alkynes

Cited by 23 publications

References 16 publications

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

Covalent protein modification: the current landscape of residue-specific electrophiles

Chemical Protein Modification through Cysteine

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