Inhibition of the serine proteases leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin by peptide boronic acids.

Kettner, Charles A.; Shenvi, Ashok B.

doi:10.1016/s0021-9258(17)42521-x

Cited by 283 publications

(151 citation statements)

References 33 publications

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“…The results reported for the specific boronic acids (e.g. BzB, I) invite comparison with the peptide boronic acids that are slow-binding inhibitors of serine proteinases; the slow step is believed to be a change in conformation of the enzyme (Kettner & Shenvi, 1984). Some of these latter inhibitors bind very tightly, with K1* below 1 nM; none of our inhibitors binds to the ,3-lactamases with such a high affinity.…”

Section: Discussionmentioning

confidence: 69%

β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids

Crompton

Cuthbert

Lowe

et al. 1988

Biochemical Journal

100

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Many beta-lactamases have active-site serine residues, and are competitively inhibited by boronic acids. Hitherto, the boronic acids used have lacked any structural resemblance to the substrates of beta-lactamases. Phenylacetamidomethaneboronic acid, trifluoroacetamidomethaneboronic acid and 2,6-dimethoxybenzamidomethaneboronic acid have now been synthesized. The first of these contains the side-chain moiety of penicillin G, and the last that of methicillin. The pH-dependence of binding of the first inhibitor to beta-lactamase I from Bacillus cereus revealed pK values of 4.7 and 8.2 for (presumably) active-site groups in the enzyme. The kinetics of inhibition were studied by cryoenzymology and by stopped-flow spectrophotometry. These techniques provided evidence for a two-step mechanism of binding of the first two boronic acids mentioned above to beta-lactamase I, and for benzeneboronic acid to a beta-lactamase from Pseudomonas aeruginosa. The slower step is probably associated with a change in enzyme conformation as well as the formation of an O-B bond between the active-site serine hydroxy group and the boronic acid.

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Section: Discussionmentioning

confidence: 69%

β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids

Crompton

Cuthbert

Lowe

et al. 1988

Biochemical Journal

100

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show abstract

“…sodium borate) and synthetic (i.e. peptide boronic acid) boron compounds have been shown to inhibit serine proteases such as chymotrypsin, cathepsin G, elastase in a reversible manner in vitro [7,54,55]. The inhibition of serine proteases in coagulation system by boron, which is another way of action of boron in inflammatory response, has also been suggested [56].…”

Section: Boron In Human and Animal Healthmentioning

confidence: 99%

The importance of boron in biological systems

Uluışık

Karakaya

Koç

2018

Journal of Trace Elements in Medicine and Biology

219

128

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Boron is an essential element for plants and probably essential for human and animal health. Boron has a broad range of physiological effects on biological systems at low concentrations, whereas it is toxic to at high concentrations. Eventhough there are many studies on boron's biological effects and toxicity, more information is needed to understand the mechanisms of its action. The aim of the current work is to review boron's function, transport and toxicity in different biological systems.

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“…Nitriles and boronic acids can react with other proteins containing catalytic or noncatalytic nucleophilic residues amenable for covalent modification [ 45 , 46 , 47 , 48 ]. Inhibition of unrelated serine esterases, i.e., human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with catalytic serine, human caspase-1 with catalytic cysteine, and human monoamine oxidases A and B (hMAO-A/B) with tractable cysteines at the active site [ 49 ] was investigated with selected compounds ( Table S6 ).…”

Section: Resultsmentioning

confidence: 99%

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Kollár

Gobec

Proj

et al. 2021

Cells

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Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.

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Inhibition of the serine proteases leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin by peptide boronic acids.

Cited by 283 publications

References 33 publications

β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids

β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids

The importance of boron in biological systems

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

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