Computational Approaches in the Rational Design of Improved Carbonyl Quenchers: Focus on Histidine Containing Dipeptides

Vistoli, Giulio; Colzani, Mara; Mazzolari, Angelica; Maddis, Danilo De; Grazioso, Giovanni; Pedretti, Alessandro; Carini, Marina

doi:10.4155/fmc-2016-0088

Cited by 19 publications

(15 citation statements)

References 38 publications

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“…This will also suppress the regeneration of NAD + for ongoing glycolysis. It is known that carnosine does react with aldehydes [34], or as other histidine containing dipeptides, with carbonyl groups in general [35]. Therefore, it may react with one or several metabolites in the glycolytic pathway.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate attenuates the anti-neoplastic effect of carnosine independently from oxidative phosphorylation

et al. 2016

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Here we analyzed whether the anti-neoplastic effect of carnosine, which inhibits glycolytic ATP production, can be antagonized by ATP production via oxidative phosphorylation fueled by pyruvate. Therefore, glioblastoma cells were cultivated in medium supplemented with glucose, galactose or pyruvate and in the presence or absence of carnosine. CPI-613 was employed to inhibit the entry of pyruvate into the tricarboxylic acid cycle and 2,4-dinitrophenol to inhibit oxidative phosphorylation. Energy metabolism and viability were assessed by cell based assays and histochemistry.ATP in cell lysates and dehydrogenase activity in living cells revealed a strong reduction of viability under the influence of carnosine when cells received glucose or galactose but not in the presence of pyruvate. CPI-613 and 2,4-dinitrophenol reduced viability of cells cultivated in pyruvate, but no effect was seen in the presence of glucose. No effect of carnosine on viability was observed in the presence of glucose and pyruvate even in the presence of 2,4-dinitrophenol or CPI-613.In conclusion, glioblastoma cells produce ATP from pyruvate via the tricarboxylic acid cycle and oxidative phosphorylation in the absence of a glycolytic substrate. In addition, pyruvate attenuates the anti-neoplastic effect of carnosine, even when ATP production via tricarboxylic acid cycle and oxidative phosphorylation is blocked. We also observed an inhibitory effect of carnosine on the tricarboxylic acid cycle and a stimulating effect of 2,4-dinitrophenol on glycolytic ATP production.

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Section: Discussionmentioning

confidence: 99%

Pyruvate attenuates the anti-neoplastic effect of carnosine independently from oxidative phosphorylation

et al. 2016

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“…Calculations also included the resolved amyloid fibril (PDB Id: 2MXU). The ligands were simulated in their keto-enolic form and their conformational space was explored by combining MonteCarlo simulations and PM7-based semi-empirical minimizations as previously described 46 . In detail, the amyloid monomer was minimized by keeping fixed the backbone atoms to preserve the resolved folding and utilized to build the corresponding dimer by following the computational procedure as described by Rao and co-workers 47 .…”

Section: Z5e-4-hydroxy-6-(4-hydroxy-3-methoxyphenylmentioning

confidence: 99%

Prenylated Curcumin Analogues as Multipotent Tools To Tackle Alzheimer’s Disease

Bisceglia

Seghetti

Serra

et al. 2018

ACS Chem. Neurosci.

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Alzheimer's disease is likely to be caused by copathogenic factors including aggregation of Aβ peptides into oligomers and fibrils, neuroinflammation and oxidative stress. To date, no effective treatments are available and because of the multifactorial nature of the disease, it emerges the need to act on different and simultaneous fronts. Despite the multiple biological activities ascribed to curcumin as neuroprotector, its poor bioavailability and toxicity limit the success in clinical outcomes. To tackle Alzheimer's disease on these aspects, the curcumin template was suitably modified and a small set of analogues was attained. In particular, derivative 1 turned out to be less toxic than curcumin. As evidenced by capillary electrophoresis and transmission electron microscopy studies, 1 proved to inhibit the formation of large toxic Aβ oligomers, by shifting the equilibrium towards smaller non-toxic assemblies and to limit the formation of insoluble fibrils. These findings were supported by molecular docking and steered molecular dynamics simulations which confirmed the superior capacity of 1 to bind Aβ structures of different complexity. Remarkably, 1 also showed in vitro anti-inflammatory and anti-oxidant properties. In summary, the curcumin-based analogue 1 emerged as multipotent compound worth to be further investigated and exploited in the Alzheimer's disease multi-target context.

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“…Hence, the rational design of improved l-carnosine derivatives should be focused on molecules that, besides maintaining or even enhancing quenching activity and selectivity, are endowed with plasma stability and oral bioavailability. To this end, the ideal derivative should: (a) maintain or better optimize its quenching activity, at least toward HNE, while preserving its selectivity; (b) maintain the active transport by human H + /peptide cotransporter-1 (hPepT1); and (c) eliminate recognition by human serum carnosinase (30,31). As depicted in Figure 1A, this can be pursued by modifying the carboxyl group, which (a) is not involved in the quenching mechanism, even though its complete deletion has a detrimental effect, as seen in carcinine; (b) has a crucial role in carnosinase-1 (CN1) binding ( Figure 1B); and (c) has a marginal role in hPepT1 transport ( Figure 1C).…”

Section: Introductionmentioning

confidence: 99%

A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress

Anderson

Vistoli

Katunga

et al. 2018

Journal of Clinical Investigation

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Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.

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Computational Approaches in the Rational Design of Improved Carbonyl Quenchers: Focus on Histidine Containing Dipeptides

Abstract: This study confirms that in silico approaches can be successfully used in the rational design of improved carbonyl quenchers. Physicochemical and stereoelectronic descriptors appear really informative especially when explored by their corresponding property spaces.

Cited by 19 publications

References 38 publications

Pyruvate attenuates the anti-neoplastic effect of carnosine independently from oxidative phosphorylation

Pyruvate attenuates the anti-neoplastic effect of carnosine independently from oxidative phosphorylation

Prenylated Curcumin Analogues as Multipotent Tools To Tackle Alzheimer’s Disease

A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress

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