Structural and Functional Properties, Chaperone Activity and Posttranslational Modifications of Alpha-Crystallin and its Related Subunits in the Crystalline Lens: N-acetylcarnosine, Carnosine and Carcinine act as Alpha- Crystallin/Small Heat Shock Protein Enhancers in Prevention and Dissolution of Cataract in Ocular Drug Delivery Formulations of Novel Therapeutic Agents

Abstract

Cataract is a leading cause of blindness worldwide and is responsible for ∼40-80% of the estimated 45 million cases of blindness that occur across the globe. In addition to providing refractive properties to the lens for focusing the image, it is believed that the molecular chaperone function of α-crystallin is essential in preventing the light scattering due to aggregation of other proteins and thus in the maintenance of lens transparency and thereby prevention of cataract. By now, it is fairly acknowledged that chaperoning ability of α-crystallin is instrumental in the maintenance of crystalline lens transparency, and decreased chaperone-like activity of α-crystallin is associated with various types and stages of cataract. A better pharmacological targeting of safeguarding the α-crystallin chaperone activity may aid the development of therapeutic strategies that could evade the need for cataract surgery and revive lens transparency of the cataractous lenses. This article originally summarizes the significance of modulation and enhancing of α-crystallin chaperone activity with imidazole-containing dipeptides N-acetylcarnosine, carnosine and carcinine in consequence to prevent, delay or dissolve the human cataract. A growing evidence and discussion of recent patents are presented in this study that demonstrate the ability of N-acetylcarnosine (lubricant eye drops) or carcinine (lubricant eye drops) (universal antioxidant and deglycation agent) resistant to enzymatic hydrolysis with carnosinase to act as pharmacological chaperones, to decrease oxidative stress and ameliorate oxidative and excessive glycation stress-related eye disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for age-related cataracts, age-related macular degeneration (AMD) and ocular complications of diabetes (OCD). The therapeutic strategies are highlighted in the study for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human age-related eye disease, such as cataracts and advanced glycation tissue proteins - engineered systems.

An Increase in Phosphorylation and Truncation of Crystallin With the Progression of Cataracts

“…Ischemic diabetic retinopathy might protect against nuclear sclerotic cataracts, and these findings were consistent with the hypothesis that increased exposure to oxygen is responsible for nuclear cataract formation 33 . None of the patients in this study used these drugs regularly, but the relations of these drugs’ antioxidative function and the crystalline changes noted in this study are worthy of advanced studies 34 . In contrast, 2 well-known drugs, corticosteroids 35 and the antipsychotic drug quetiapine, 36 can induce cataracts; none of our patients received these drugs for >1 month; therefore, they were not the issues of our study.…”

Current Approach to the Pathogenesis of Diabetic Cataracts

“…There are numerous reports on the reduced protective activity of α-crystallins in the lenses of diabetic patients compared to the lenses of non-diabetic patients [ 76 , 77 , 78 ]. Therefore, many studies [ 75 , 77 , 79 ] have aimed to develop protective factors for the specific qualities of α-crystallins, with the goals of understanding the cause of cataracts and developing potential treatments.…”

Biophysical Insights into Implications of PEG-400 on the α-Crystallin Structure: Multispectroscopic and Microscopic Approach

“…The decreased chaperone-like activity of α-crystallin is associated with various types and stages of cataract, highlighting the therapeutic potential of α-crystallin in cataract treatment. 13 α-Crystallin serves as the molecular chaperone, acting as a defense, preventing aggregation of damaged/aged lens proteins and enzymes that would otherwise lead to light scattering thereby leading to cataract formation. This chaperone-like activity (CLA) of α-crystallin is vital for lens transparency and it is hypothesized that cataract can be slowed down by maintaining optimal or increasing chaperone activity.…”

“…The decreased chaperone-like activity of α-crystallin is associated with various types and stages of cataract, highlighting the therapeutic potential of α-crystallin in cataract treatment. 13 activity (CLA) of α-crystallin is vital for lens transparency and it is hypothesized that cataract can be slowed down by maintaining optimal or increasing chaperone activity. According to a study, small molecule pharmacological agents from natural sources can prevent the loss of CLA of α-crystallin Achain (AAC), leading to a delay in cataract formation in preclinical models.…”

“…The importance of α-crystallin in cataract can be owed to the fact that the chaperoning ability of α-crystallin is influential in maintaining lens transparency which ultimately plays a role in cataract. The decreased chaperone-like activity of α-crystallin is associated with various types and stages of cataract, highlighting the therapeutic potential of α-crystallin in cataract treatment . α-Crystallin serves as the molecular chaperone, acting as a defense, preventing aggregation of damaged/aged lens proteins and enzymes that would otherwise lead to light scattering thereby leading to cataract formation.…”