Solid-Phase Synthesis of Peptide Vinyl Sulfones as Potential Inhibitors and Activity-Based Probes of Cysteine Proteases

Wang, Gang; Uttamchandani, Mahesh; Chen, Grace Y. J.; Yao, Shao Q.

doi:10.1021/ol0275567

Cited by 103 publications

(34 citation statements)

References 16 publications

(28 reference statements)

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“…[8] ABPs also allow affinity purification of corresponding enzymes. [8] Our laboratory and others have extensively investigated epoxysuccinates, [5,[9][10][11] vinyl sulfones, [9,12] and, more recently, AOMKs [13] as ABPs. While these probes have proven useful for a number of biological applications, they all have limitations resulting from complex synthetic methods or scope of targets that can be analyzed.…”

Section: Introductionmentioning

confidence: 99%

Novel Aza Peptide Inhibitors and Active‐Site Probes of Papain‐Family Cysteine Proteases

et al. 2006

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Recent characterization of multiple classes of functionalized azapeptides as effective covalent inhibitors of cysteine proteases prompted us to investigate O‐acyl hydroxamates and their azapeptide analogues for use as activity‐based probes (ABPs). We report here a new class of azaglycine‐containing O‐acylhydroxamates that form stable covalent adducts with target proteases. This allows them to be used as ABPs for papain family cysteine proteases. A second class of related analogues containing a novel O‐acyl hydroxyurea warhead was found to function as covalent inhibitors of papain‐like proteases. These inhibitors can be easily synthesized on solid support, which allows rapid optimization of compounds with improved selectivity and potency for a given target enzyme. We present here one such optimized inhibitor that showed selective inhibition of falcipain 1, a protease of the malaria‐causing parasite, Plasmodium falciparum.

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Section: Introductionmentioning

confidence: 99%

Novel Aza Peptide Inhibitors and Active‐Site Probes of Papain‐Family Cysteine Proteases

et al. 2006

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“…The tag may incorporate a moiety, such as an alkyne or azide, for subsequent modification, such as by the Cu(I)-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC), to introduce a reporter (15,16). ABPP probes have been developed to monitor changes of specific enzymes associated with certain biological states, including serine hydrolases (17,18), cysteine proteases (19)(20)(21)(22), protein phosphatases (23)(24)(25), oxidoreductases (26), histone deacetylases (27), kinases (28,29), metalloproteases (30)(31)(32), and glycosidases (33)(34)(35)(36).…”

mentioning

confidence: 99%

Cell-permeable probe for identification and imaging of sialidases

Tsai

Yen

Lin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Alkyne-hinged 3-fluorosialyl fluoride (DFSA) containing an alkyne group was shown to be a mechanism-based target-specific irreversible inhibitor of sialidases. The ester-protected analog DFSA (PDFSA) is a membrane-permeable precursor of DFSA designed to be used in living cells, and it was shown to form covalent adducts with virus, bacteria, and human sialidases. The fluorosialyl–enzyme adduct can be ligated with an azide-annexed biotin via click reaction and detected by the streptavidin-specific reporting signals. Liquid chromatography-mass spectrometry/mass spectrometry analysis on the tryptic peptide fragments indicates that the 3-fluorosialyl moiety modifies tyrosine residues of the sialidases. DFSA was used to demonstrate influenza infection and the diagnosis of the viral susceptibility to the anti-influenza drug oseltamivir acid, whereas PDFSA was used for in situ imaging of the changes of sialidase activity in live cells.

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“…The ratio of trans/cis was determined to be approximately 4/1 based on HPLC analysis with the ratio being highly dependant on the steric properties of the P1 sidechain as has been shown for peptide vinyl sulfones. 22 The desired compound with trans-conformation (yzm09, 5a) was separated by HPLC in reasonable yield (36 % for 5 steps). The labeled analogs of yzm09 were prepared from the Boc-protected compound 5b.…”

Section: Evaluation Of the αβ Unsaturated Ketone As A Warhead For Usmentioning

confidence: 99%

Evaluation of α,β-unsaturated ketone-based probes for papain-family cysteine proteases

Yang

Fonović

Verhelst

et al. 2009

Bioorganic & Medicinal Chemistry

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The field of activity based proteomics makes use of small molecule active site probes to monitor distinct subsets of enzymatic proteins. While a number of reactive functional groups have been applied to activity based probes (ABPs) that target diverse families of proteases, there remains a continual need for further evaluation of new probe scaffolds and reactive functional groups for use in ABPs. In this study we evaluate the utility of the α, β-unsaturated ketone reactive group for use in ABPs targeting the papain family of cysteine proteases. We find that this reactive group shows highly selective labeling of cysteine cathepsins in both intact cells and total cell extracts. We observed a variable degree of background labeling that depended on the type of tag and liker used in the probe synthesis. The relative ease of synthesis of this class of compounds provides the potential for further derivatization to generate new families of cysteine protease ABPs with unique specificity and labeling properties.

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Solid-Phase Synthesis of Peptide Vinyl Sulfones as Potential Inhibitors and Activity-Based Probes of Cysteine Proteases

Cited by 103 publications

References 16 publications

Novel Aza Peptide Inhibitors and Active‐Site Probes of Papain‐Family Cysteine Proteases

Novel Aza Peptide Inhibitors and Active‐Site Probes of Papain‐Family Cysteine Proteases

Cell-permeable probe for identification and imaging of sialidases

Evaluation of α,β-unsaturated ketone-based probes for papain-family cysteine proteases

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