DNA-aptamers raised against AGEs as a blocker of various aging-related disorders

Abstract

A non-enzymatic reaction between sugars or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules, which could impair their structural integrity and function. This process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions, such as rearrangements and dehydration to become irreversibly crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress in a physiological aging process and at an accelerated rate under hyperglycemic, inflammatory and oxidative stress conditions. There is a growing body of evidence that AGEs and their receptor RAGE interaction play a role in the pathogenesis of various devastating disorders, including cardiovascular disease, Alzheimer's disease, insulin resistance, osteoporosis and cancer growth and metastasis. Furthermore, diet has been recently recognized as a major environmental source of AGEs that could also elicit pro-inflammatory reactions, thereby being involved in organ damage in vivo. Therefore, inhibition of AGE formation and/or blockade of the interaction of AGEs with RAGE may be a novel therapeutic target for aging-related disorders. This article discusses a potential utility of DNA-aptamers raised against AGEs for preventing aging and/or diabetes-associated organ damage, especially focusing on diabetic microvascular complications, vascular remodeling, metabolic derangements, and melanoma growth and expansion in animal models.

The challenges of glycan recognition with natural and artificial receptors

“…DNA aptamers have also been produced against advanced glycation end (AGE) products to target macromolecules associated with age related disorders. 161 Although results were promising, it was stated that further testing of the aptamers needed to be performed for safety and efficacy, before consideration for clinical use.…”

RAGE-Aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy

“…We have already shown that glyceraldehyde-modified AGEs contribute to diabetic complications in animal models and that their circulating levels are correlated with endothelial dysfunction and inflammatory biomarkers in high-risk patients, including those with diabetes (27,28,36,47,48). Furthermore, in glyceraldehyde-modified AGEs bound to vRAGE with a K d of 8.60 nmol/L (Fig.…”

<p>Aptamers as Versatile Ligands for Biomedical and Pharmaceutical Applications</p>

“…14 Presently, only one aptamer drug (Macugen) has been approved by the FDA, but several others are being evaluated in clinical trials. 15 In addition, aptamers have been used to treat aging-related disorders, 16 obesity and diabetes mellitus, 17,18 cardiovascular diseases, 19 infectious diseases, 20,21 blood coagulation, 22 bone diseases, 23 immunological diseases, 24 and cancers 25 (Figure 2).…”