Bendazac prevents cyanate binding to soluble lens proteins and cyanate-induced phase-separation opacities in vitro: a possible mechanism by which bendazac could delay cataract

doi:10.1016/0014-4835(86)90075-8

Experimental Eye Research

Volume 43, Issue 6, December 1986, Pages 973-979

https://doi.org/10.1016/0014-4835(86)90075-8 Get rights and content

Abstract

The reaction of lens proteins with cyanate (carbamylation) causes many changes seen in human cataract including disruption of the protein conformations. Bendazac, a putative anti-cataract drug, decreases the binding of cyanate to lens proteins and prevents the cyanate-induced elevation of the phase separation temperature in incubated rat lenses. Its major metabolite, 5-hydroxybendazac, also inhibits the binding of cyanate to lens proteins even when it is present only during a pre-incubation period. The metabolite is more effective than the parent compound.

References (14)

M. Crompton et al.
Aspirin prevents carbamylation of soluble lens proteins and prevents cyanate-induced phase-separation opacities in vitro: a possible mechanism by which aspirin could prevent cataract
Exp. Eye Res.
(1985)
J.J. Harding et al.
The lens: development, proteins, metabolism and cataract
J.J. Harding et al.
Carbamylation of lens proteins: a possible factor in cataractogenesis in some countries
Exp. Eye Res.
(1980)
D.C. Minassian et al.
Dehydrational crises from severe diarrhoea or heatstroke and risk of cataract
Lancet
(1984)
L. Pandolfo et al.
Effects of bendazac l-lysine salt on X-ray-induced cataract in the rabbit lens
Exp. Eye Res.
(1986)
M. Testa et al.
Pilot study of bendazac for treatment of cataract
Lancet
(1982)
H.T. Beswick et al.
Conformational changes induced in bovine lens alpha-crystallin by carbamylation. Relevance to cataract
Biochem. J.
(1984)

There are more references available in the full text version of this article.

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Citation Excerpt :
Eicosapentaenoic acid supplementation in mice decreased mitochondrial protein carbamylation (Johnson et al., 2015), and triclosan similarly inhibited carbamylation (Bright et al., 2018). Aspirin, ibuprofen, and bendazac have all been shown to inhibit carbamylation events that commonly pathologically occur on lens proteins (Crompton et al., 1985; Lewis et al., 1986; Plater et al., 1997; Rao and Cotlier, 1988). Again, these studies are either in vitro or animal studies, and have not been translated to clinical applications and serve as areas for future investigation.
Non-enzymatic post-translational modifications (nPTMs) of proteins have emerged as novel risk factors for the genesis and progression of various diseases. We now have a variety of experimental and established therapeutic strategies to target harmful nPTMs and potentially improve clinical outcomes. Protein carbamylation and glycation are two common and representative nPTMs that have gained considerable attention lately as favorable therapeutic targets with emerging clinical evidence. Protein carbamylation is associated with the occurrence of cardiovascular disease (CVD) and mortality in patients with chronic kidney disease (CKD); and advanced glycation end products (AGEs), a heterogeneous group of molecules produced in a series of glycation reactions, have been linked to various diabetic complications. Therefore, reducing the burden of protein carbamylation and AGEs is an appealing and promising therapeutic approach.
This review chapter summarizes potential anti-nPTM therapy options in CKD, CVD, and diabetes along with clinical implications. Using two prime examples—protein carbamylation and AGEs—we discuss the varied preventative and therapeutic options to mitigate these pathologic nPTMs in detail. We provide in-depth case studies on carbamylation in the setting of kidney disease and AGEs in metabolic disorders, with an emphasis on the relevance to reducing adverse clinical outcomes such as CKD progression, cardiovascular events, and mortality. Overall, whether specific efforts to lower carbamylation and AGE burden will yield definitive clinical improvement in humans remains largely to be seen. However, the scientific rationale for such pursuits is demonstrated herein.
Protein Carbamylation in Chronic Kidney Disease and Dialysis
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Protein carbamylation is a nonenzymatic posttranslational protein modification that can be driven, in part, by exposure to urea's dissociation product, cyanate. In humans, when kidney function is impaired and urea accumulates, systemic protein carbamylation levels increase. Additional mediators of protein carbamylation have been identified including inflammation, diet, smoking, circulating free amino acid levels, and environmental exposures. Carbamylation reactions on proteins are capable of irreversibly changing protein charge, structure, and function, resulting in pathologic molecular and cellular responses. Carbamylation has been mechanistically linked to the biochemical pathways implicated in atherosclerosis, dysfunctional erythropoiesis, kidney fibrosis, autoimmunity, and other pathological domains highly relevant to patients with chronic kidney disease. In this review, we describe the biochemical impact of carbamylation on human proteins, the mechanistic role carbamylation can have on clinical outcomes in kidney disease, the clinical association studies of carbamylation in chronic kidney disease, including patients on dialysis, and the promise of therapies aimed at reducing carbamylation burden in this vulnerable patient population.
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2010, Bioorganic and Medicinal Chemistry Letters
Novel bendazac analogues and their salts have been designed and prepared. The resulting compounds (13c–d, 15c, 17c) showed very good aqueous solubility (>100 mg/mL). An in vitro assay showed that most of the resulting compounds had potent protective activity against the oxidative damage. Particularly, compound 13d was also able to enhance the WSP and T-AOC level in the H₂O₂/FeCl₃-induced oxidative damage model, indicating the resulting compound may protect the lens through an antioxidant pathway.
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However, ibuprofen has no acetyl group, and a different mechanism may apply. Bendazac also inhibits the carbamylation of lens protein when present with cyanate [180]. The targeting of the uptake via scavenger receptors seems to be more achievable and clinically used statins and PPAR gamma ligands were shown to be partially effective in mice to control scavenger receptor expression and functionality [181, 182].
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‘Condensation diseases’ are heterogeneous pathological conditions in which the primary pathogenetic step is the loss of solubility of specific substances, resulting in the formation of a condensed phase. Typical examples are cataract, nephrolithiasis, gallstone disease and certain rheumatic conditions in which protein denaturation, aggregation and precipitation may occur. Since the condensing molecules are often proteins, antidenaturant agents should be considered rational drugs for the treatment of these diseases. Surprisingly, however, only a few molecules with these properties are currently available for therapeutic use, including bendazac for cataract.
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1996, Biochemical and Biophysical Research Communications
The involvement of near-UV light in cataract development suggests that potential anti-cataract drugs may display unusual spectroscopic properties. As bendazac impedes certain effects associated with lens opacification, we have characterized the singlet and triplet states of bendazac and its analog, benzydamine, by fluorescence and phosphorescence methods. These compounds have much shorter triplet state lifetimes compared to the triplet state lifetimes observed in proteins. Our results raise the possibility that the photoprotective action of these compounds may result from their ability to dissipate energy through the triplet state. We propose alternative modes for the photoprotective actions of these compounds.

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Bendazac prevents cyanate binding to soluble lens proteins and cyanate-induced phase-separation opacities in vitro: a possible mechanism by which bendazac could delay cataract

Abstract

Exp. Eye Res.

Exp. Eye Res.

Lancet

Exp. Eye Res.

Lancet

Conformational changes induced in bovine lens alpha-crystallin by carbamylation. Relevance to cataract

Biochem. J.