Carnosine derivatives: new multifunctional drug-like molecules

Bellia, Francesco; Vecchio, Graziella; Rizzarelli, Enrico

doi:10.1007/s00726-011-1178-6

Cited by 51 publications

(48 citation statements)

References 70 publications

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“…It is found in excitable tissues such as the myocardium, skeletal muscles and brain, but it is normally destroyed by the enzyme carnosinase. Normally, carnosinase acts fast and reduces the serum levels of carnosine, thus diminishing its effectiveness in clinical treatments 21. There have been attempts at stabilizing carnosine against carnosinase degradation, for example, by conjugating it with vitamin E derivatives44 or small sugars,45, 46 but research in this area is still underway.…”

Section: Discussionmentioning

confidence: 99%

Carnosine Inhibits Aβ₄₂ Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster

et al. 2013

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Aggregation of the amyloid-β peptide (Aβ) into fibrillar structures is a hallmark of Alzheimer's disease. Thus, preventing self-assembly of the Aβ peptide is an attractive therapeutic strategy. Here, we used experimental techniques and atomistic simulations to investigate the influence of carnosine, a dipeptide naturally occurring in the brain, on Aβ aggregation. Scanning force microscopy, circular dichroism and thioflavin T fluorescence experiments showed that carnosine does not modify the conformational features of Aβ42 but nonetheless inhibits amyloid growth. Molecular dynamics (MD) simulations indicated that carnosine interacts transiently with monomeric Aβ42 by salt bridges with charged side chains, and van der Waals contacts with residues in and around the central hydrophobic cluster ((17)LVFFA(21)). NMR experiments on the nonaggregative fragment Aβ12-28 did not evidence specific intermolecular interactions between the peptide and carnosine, in agreement with MD simulations. However, a close inspection of the spectra revealed that carnosine interferes with the local propensity of the peptide to form backbone hydrogen bonds close to the central hydrophobic cluster (residues E22, S26 and N27). Finally, MD simulations of aggregation-prone Aβ heptapeptide segments show that carnosine reduces the propensity to form intermolecular backbone hydrogen bonds in the region 18-24. Taken together, the experimental and simulation results (cumulative MD sampling of 0.2 ms) suggest that, despite the inability of carnosine to form stable contacts with Aβ, it might block the pathway toward toxic aggregates by perturbing the hydrogen bond network near residues with key roles in fibrillogenesis.

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Section: Discussionmentioning

confidence: 99%

Carnosine Inhibits Aβ₄₂ Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster

et al. 2013

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“…The homeostasis of this dipeptide in the skeletal muscle is maintained by transporters PHT1, PEPT 2 and Taut [50-52]. In addition to its ability to react with HNE and acrolein, carnosine chelates transition metals, for example, Cu 2+ and Fe 2+ , and buffers intracellular pH [53]. …”

Section: Nutraceuticals As Biogenic Aldehyde Scavengersmentioning

confidence: 99%

Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease

Nelson

Baba

Anderson

2017

Current Opinion in Pharmacology

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Aldehydes are continuously formed in biological systems through enzyme-dependent and spontaneous oxidation of lipids, glucose, and primary amines. These highly reactive, biogenic electrophiles can become toxic via covalent modification of proteins, lipids and DNA. Thus, agents that scavenge aldehydes through conjugation have therapeutic value for a number of major cardiovascular diseases. Several commonly-prescribed drugs (e.g., hydralazine) have been shown to have potent aldehyde-conjugating properties which may contribute to their beneficial effects. Herein, we briefly describe the major sources and toxicities of biogenic aldehydes in cardiovascular system, and provide an overview of drugs that are known to have aldehyde-conjugating effects. Some compounds of phytochemical origin, and histidyl-dipeptides with emerging therapeutic value in this area are also discussed.

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“…On the other hand, for clinical relevance, the use of CAR and its in vivo actions are limited inhumans due to its hydrolysis by serum carnosinase. L‐CAR derivativessuch as D‐CAR and N‐acetyl‐CAR known to resist carnosinase have been reported to be beneficial for human use (Bellia, Vecchio, & Rizzarelli, ; Hipkiss, ). In addition, chronic supplementation of CAR is found to increase its serum level through saturation of human carnosinase (De Courten et al., ).…”

Section: Discussionmentioning

confidence: 99%

Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D-galactose-induced aged rats

et al. 2017

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D-Galactose is shown to mimic natural ageing in rodents by exacerbating oxidative stress and glycation. Steroid production and having a poor antioxidant system make testis vulnerable to galactose-induced ageing. Antioxidation and antiglycating actions of carnosine may be intriguing for prevention of testicular ageing. In this study, male Wistar rats were applied D-galactose (300 mg/kg; subcutaneously 5 days a week) and carnosine (250 mg/kg; intraperitoneally 5 days a week) along with D-galactose for 2 months. D-Galactose treatment increased testicular reactive oxygen species, thiobarbituric acid reactive substances, diene conjugates, protein carbonyls, advanced oxidation products of proteins and advanced glycation end products. Carnosine was capable of repelling oxidative stress and glycation produced by D-galactose. Johnsen's score, which describes histopathological evaluation, was also significantly improved with preserved spermatogenesis by carnosine. It appears that carnosine deters the testicular oxidative stress due to galactose-induced ageing directly by its antioxidative and antiglycating properties.

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Carnosine derivatives: new multifunctional drug-like molecules

Cited by 51 publications

References 70 publications

Carnosine Inhibits Aβ₄₂ Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster

Carnosine Inhibits Aβ₄₂ Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster

Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease

Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D-galactose-induced aged rats

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Carnosine derivatives: new multifunctional drug-like molecules

Cited by 51 publications

References 70 publications

Carnosine Inhibits Aβ42 Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster

Carnosine Inhibits Aβ42 Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster

Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease

Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D-galactose-induced aged rats

Contact Info

Product

Resources

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Carnosine Inhibits Aβ₄₂ Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster

Carnosine Inhibits Aβ₄₂ Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster