A Template‐Based Approach to Inhibitors of Calpain 2, 20S Proteasome, and HIV‐1 Protease

Jones, Seth; Neilsen, Paul M.; Siew, Limei; Callen, David F.; Goldfarb, Nathan E.; Dunn, Ben M.; Abell, Andrew D.

doi:10.1002/cmdc.201300387

Cited by 10 publications

(2 citation statements)

References 59 publications

(34 reference statements)

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“…There would be an additional advantage in generating such templates in which the P1 or P1′ residues are not part of the macrocycle. This would then allow the appendage of a range of groups at these positions (for example, amino aldehyde or amino dicarbonyl moieties)3, 4, 7, 8 to allow the targeting of a particular protease 9. The approach reported herein involves replacing two amino acids of the macrocyclic backbone of first‐generation inhibitors of type 2 with a substituted pyrrole, where this group would be expected to maintain the planar geometry required for an extended β‐strand geometry10 (see 3 – 5 , Scheme ).…”

Section: Methodsmentioning

confidence: 99%

Neutral Nickel Ethylene Oligo‐ and Polymerization Catalysts: Towards Computational Catalyst Prediction and Design

Heyndrickx

Occhipinti

Jensen

2014

Chemistry A European J

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DFT calculations have been used to elucidate the chain termination mechanisms for neutral nickel ethylene oligo- and polymerization catalysts and to rationalize the kind of oligomers and polymers produced by each catalyst. The catalysts studied are the (κ(2)-O,O)-coordinated (1,1,1,5,5,5-hexafluoro-2,4-acetylacetonato)nickel catalyst I, the (κ(2)-P,O)-coordinated SHOP-type nickel catalyst II, the (κ(2)-N,O)-coordinated anilinotropone and salicylaldiminato nickel catalysts III and IV, respectively, and the (κ(2)-P,N)-coordinated phosphinosulfonamide nickel catalyst V. Numerous termination pathways involving β-H elimination and β-H transfer steps have been investigated, and the most probable routes identified. Despite the complexity and multitude of the possible termination pathways, the information most critical to chain termination is contained in only few transition states. In addition, by consideration of the propagation pathway, we have been able to estimate chain lengths and discriminate between oligo- and polymerization catalysts. In agreement with experiment, we found the Gibbs free energy difference between the overall barrier for the most facile propagation and termination pathways to be close to 0 kcal mol(-1) for the ethylene oligomerization catalysts I and V, whereas values of at least 7 kcal mol(-1) in favor of propagation were determined for the polymerization catalysts III and IV. Because of the shared intermediates between the termination and branching pathways, we have been able to identify the preferred cis/trans regiochemistry of β-H elimination and show that a pronounced difference in σ donation of the two bridgehead atoms of the bidentate ligand can suppress hydride formation and thus branching. The degree of rationalization obtained here from a handful of key intermediates and transition states is promising for the use of computational methods in the screening and prediction of new catalysts of the title class.

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Section: Methodsmentioning

confidence: 99%

Neutral Nickel Ethylene Oligo‐ and Polymerization Catalysts: Towards Computational Catalyst Prediction and Design

Heyndrickx

Occhipinti

Jensen

2014

Chemistry A European J

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“…An i to i +2 side‐chain constraint is known to effectively stabilise a β‐strand geometry particularly in short peptides, [2a] with the constraint length being important [5a,d,8c] . With this in mind, the i,i+2 cysteine and homocysteine bimane constrained peptides 8 and 9 were prepared.…”

Section: Resultsmentioning

confidence: 99%

A Bimane‐Based Peptide Staple for Combined Helical Induction and Fluorescent Imaging

et al. 2020

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The thiol-selective fluorescent imaging agent, dibromobimane, has been repurposed to crosslink cysteine-and homocysteinecontaining peptides, with the resulting bimane linker acting as both a structural constraint and a fluorescent tag. Macrocyclisation was conducted on nine short peptides containing two cysteines and/or homocysteines, both on-resin and in buffered aqueous solution, to give macrocycles ranging in size from 16 (i,i + 2) to 31 (i,i + 7) atoms. The structures were defined by CD, NMR structure calculations by using Xplor-NIH, NMR secondary shift and J HαNH analyses to reveal helical structure in the i,i + 4 (1, 2), and i,i + 3 (5) constrained peptides. Cellularuptake studies were conducted with three of the macrocycles. Subsequent confocal imaging revealed punctate fluorescence within the cytosol indicative of peptides trapped in endocytic vesicles. These studies demonstrate that dibromobimane is an effective tool for defining secondary structure within short peptides, whilst simultaneously introducing a fluorescent tag suitable for common cell-based experiments.

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Macrocyclic Protease Inhibitors with Reduced Peptide Character

et al. 2014

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There is a real need for simple structures that define a β‐strand conformation, a secondary structure that is central to peptide–protein interactions. For example, protease substrates and inhibitors almost universally adopt this geometry on active site binding. A planar pyrrole is used to replace two amino acids of a peptide backbone to generate a simple macrocycle that retains the required geometry for active site binding. The resulting β‐strand templates have reduced peptide character and provide potent protease inhibitors with the attachment of an appropriate amino aldehyde to the C‐terminus. Picomolar inhibitors of cathepsin L and S are reported and the mode of binding of one example to the model protease chymotrypsin is defined by X‐ray crystallography.

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A Template‐Based Approach to Inhibitors of Calpain 2, 20S Proteasome, and HIV‐1 Protease

Cited by 10 publications

References 59 publications

Neutral Nickel Ethylene Oligo‐ and Polymerization Catalysts: Towards Computational Catalyst Prediction and Design

Neutral Nickel Ethylene Oligo‐ and Polymerization Catalysts: Towards Computational Catalyst Prediction and Design

A Bimane‐Based Peptide Staple for Combined Helical Induction and Fluorescent Imaging

Macrocyclic Protease Inhibitors with Reduced Peptide Character

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