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Potential break through technology poised
With regards to translational development of SMEPT, we acknowledge that we are not aware of any trials currently underway to validate this methodology in clinical settings. It appears fair to say that enthusiasm and commitment from corporate developers does not match that of academic partners. One reason for a dampened interest of corporate partners in SMEPT (revealed to us in private communication) is the envisioned hurdles of regulatory approval. Specifically, for success of SMEPT, approval is needed for the biocatalytic implant and also for the administered prodrug, effectively presenting a “double trouble” approval prospect. However, we hope that this review would spur broader, well-deserved interest in SMEPT, specifically in light of most recent developments in the field. Good example is the successful design of implantable biomaterials for localized synthesis of nitric oxide, which effectively creates a rifadin for such products and their associated unique functionality. Acceptance of SMEPT may be further facilitated by the use endogenous compounds as prodrugs, as was already achieved for generation of nitric oxide using natural RSNO [52], [55].

Enzyme prodrug therapy mediated by implantable biomaterials combines the benefits offered by the site specific drug delivery techniques and the systemic administration of drugs. From the former, SMEPT inherits the localized mode of drug delivery with lower systemic distribution of the drug and hence lower side effects. From the latter, SMEPT enjoys the flexibility of changing treatment in terms of drug dosage, duration of treatment, sequential or combination treatments. In vitro and in vivo validation of this technology offers this platform for translational research – which is the next necessary step for a broader acceptance of this methodology, academically and clinically.

We gratefully acknowledge financial support to this work from the European Research Council Consolidator Grant (ERC-2013-CoG 617336 BTVI).

Historically, eukaryotic protein glycosylation was thought to occur exclusively in the endoplasmic reticulum and Golgi apparatus as part of the secretory pathway, which produces a vast array of diverse membrane glycoproteins. In the mid-1980s, however, Hart et al. found O-linked β-N-acetylglucosamine (O-GlcNAc) on nuclear and cytoplasmic proteins (Figure 1a) [1]. The O-GlcNAc modification is dynamic, and its addition and removal are governed by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) (Figure 1b) [2, 3, 4]. Thousands of nucleocytoplasmic proteins are substrates of these O-GlcNAc-cycling enzymes. Because O-GlcNAc levels change substantially in response to nutrient availability and multiple forms of environmental stress (e.g. hypoxia, oxidative stress, thermal stress), it is thought that O-GlcNAc cycling serves to maintain cell homeostasis by impacting cell signaling, gene expression, and proteostasis, among other processes [5,6]. Dysregulated O-GlcNAc abundance has been linked to several human diseases, including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases, and it has been speculated that OGT and OGA may be therapeutic targets [7, 8, 9, 10]. In addition, mutations in OGT have been connected to X-linked intellectual disability [11]. While the importance of O-GlcNAc cycling in metazoan physiology is by now indisputable, the functional significance of O-GlcNAc on individual substrates is extraordinarily challenging to decipher because there are so many O-GlcNAc substrates, and the rules governing substrate selection are still unclear. Therefore, methods to selectively manipulate the cellular repertoire of O-GlcNAc are currently limiting. For OGT, the challenge is compounded by the recent discovery that this enzyme uses the same active site to attach O-GlcNAc and to effect another physiologically relevant modification, the cleavage of the essential cell cycle regulator, HCF-1 (Figure 1b) [12,13]. Progress in deconvoluting the functions of the O-GlcNAc cycling enzymes depends on having structural information to guide cellular experiments. A number of major advances have been made on this front in the past five years. This review will summarize key findings of structural studies on human OGT and OGA, with our apologies for the many omissions made due to space limitations. Information about structures mentioned in the text is provided in Figure 1.
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