Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed

Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed. play in both the development and inhibition of cancer and inflammation is presented. Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed. has significantly reduced the influx of inflammatory cells to the site of injury in acute inflammation models [82]. Exogenous DS of a specific length is found to inhibit P-selectins in inflammatory mouse models [83]. On the other hand, CS is found to inhibit inflammation in rat astrocytes by preventing NF-B activation [84]. KS has been shown to ameliorate the pathological conditions associated with inflammation [85]. For example, exogenously-added KS reduced damage in cartilage explants that were exposed to interleukin-1 ex vivo. Since cartilage fragments can cause an antigenic response, resulting in an increase in inflammation and arthritic response, reduced cartilage degradation can be correlated to a reduction in the severity of arthritis [86]. In addition, when tested in vivo using a murine (S,R,S)-AHPC-PEG2-NH2 arthritis model, KS was found to ameliorate arthritis [86]. Plasma levels of KS have been identified as a potential biomarker for FHF4 joint damage in juvenile idiopathic arthritis [87]. In the cornea, KS proteoglycans are found to bind to chemokine CXCL1 and facilitate its migration into the stroma during inflammation [88]. The addition of low molecular weight KS resulted in the disruption of this KS-CXCL1 complex, leading to efflux of chemokines and (S,R,S)-AHPC-PEG2-NH2 resolution of inflammation [89]. In a study by Taniguchi and coworkers, a KS disaccharide, [SO3?-6]Gal1-4[SO3?-6]GlcNAc, prevented neutrophil-mediated inflammation and progression of emphysema in murine models, indicating its potential use for the treatment of inflammation in chronic (S,R,S)-AHPC-PEG2-NH2 obstructive pulmonary disease [90,91]. These works clearly indicate the potential of using GAGs and related (S,R,S)-AHPC-PEG2-NH2 compounds as anti-inflammatory agents. 4. GAG Mimetics Although GAGs have tremendous applications as therapeutics, there are many challenges associated with their structure, halting their success in clinical trials. As previously mentioned, GAGs are complex heterogeneous molecules with exceptional structural diversity, which not only differ in their length, but are also modified at multiple positions through sulfation, acetylation, and epimerization. This inherent heterogeneity involved in the biosynthesis of GAGs leads to a particular GAG binding to many different proteins, thus compromising selectivity and leading to side-effects when given as a therapeutic [16,92]. Furthermore, GAGs are usually obtained from animal sources. For example, heparin, one of the oldest drugs in the clinic, is obtained from porcine intestine, bovine intestine, and bovine lung. Hence, the quality of heparin obtained depends on the environmental conditions and the diet each animal is exposed to and results in significant batch-to-batch variation [93]. The heterogeneity of GAGs makes the complete characterization of every batch of heparin produced nearly impossible, thereby making quality control a daunting task [94]. In 2008, contamination of heparin with over-sulfated CS resulted in over 200 deaths and thousands of adverse effects in the United States alone [95]. To address the issues involved in the development of GAGs as therapeutics, multiple strategies have been developed to mimic GAGs through small molecules called GAG mimetics [92]. GAG mimetics have numerous advantages over GAGs as therapeutics. They are usually completely synthetic and homogenous molecules and hence are expected to have increased selectivity and fewer adverse effects [96]. They are easier to produce at large scales, design computationally, characterize, and quality control. They also have better pharmacokinetic features than GAGs, making them more drug-like. GAG mimetics can be classified into two classes: saccharide-based and non-saccharide-based. Saccharide-based GAG mimetics, although built on a sugar backbone, are synthetic and not produced from animal sources. They are less heterogeneous when compared to GAGs. On the other hand, non-saccharide-based mimetics utilize non-sugar-based scaffolds carrying negative charges through sulfates, sulfonates, carboxylates, and/or phosphates. They are completely homogenous molecules and provide numerous advantages over saccharide-based mimetics. Both saccharide and non-saccharide GAG mimetics have been developed for the treatment of cancer and inflammation, and a few are currently in clinical trials, while some are promoted in the medical center. Here, I discuss the GAG mimetics that have demonstrated amazing potential and made huge developments in the fields of malignancy and swelling. 4.1. GAG Mimetics as Anti-Cancer Providers 4.1.1. Saccharide-Based GAG MimeticsPhosphomannopentaose sulfate (PI-88; Number 3A) is an HS mimetic acquired via sulfation of the phospho-mannan complex produced from candida cultures [97]. It is a heterogeneous mixture of di- to hexa-saccharides, but mostly tetra- (60%) and penta-saccharides (30%). PI-88 potently inhibits the activity of heparanase, an enzyme that takes on a vital part in metastasis and angiogenesis. It was also found to bind to pro-angiogenic growth factors VEGF, FGF1, and FGF2 by competing with HS. Although PI-88 also possesses anticoagulant activity, in addition to anticancer activity, it appeared to be well tolerated in.