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  • Several main strategies for targeting E s described


    Several main strategies for targeting E3s described in the literature include: in vitro screening using functional assays [86]; computer programs for predicting potential druggable pockets, including those at protein-protein interfaces, and subsequent docking-based in silico ligand screening [87]; fragment-based design and further rational structure-based elaboration [43,88]. Although each approach can have several advantages, amongst the drawbacks and limitations are following: functional screening does not provide direct evidence regarding the binding site of the hits, computational methods for pocket prediction have limited reliability and also require available crystal structures (ideally of ligand-bound complexes), and fragment-based approach strongly relies on numerous biophysical techniques, requires laborious structural optimization, and is often limited by the low ligand-efficiency associated with small MCB-613 synthesis targeting protein-protein interactions. Given slow yet steady increase of solved crystal structures of RING-type E3s and their ligand-bound complexes we reasonably expect that structure-based design will prove itself as one of the most promising strategies for developing specific small molecules for targeting these enzymes. Despite the difficulties numerous RING-type E3s or their functional components have been successfully targeted in the past using small molecule modulators of protein-protein interactions, i.e. binding at substrate/receptor HIF-1α/VHL [89], p53/MDM2 and p53/MDM4 interfaces [90], adaptor/receptor interface Skp1/Skp2 [91] and several other, as reviewed in [92,93]. MDM2 is one of the most targeted E3 ligases with numerous reported synthetic inhibitors such as Nutlin-3a [94], RG7112 [95], NU8231 [96], MI-773 [97], CGM097 [98] and several others already in clinical trials as drug candidates [99] (Fig. 1B). The CRL activity modulators also emerge as a class stipulated by increasing number of solved crystal structures of CRL subunits that allows rational design of synthetic binders [92]. There is currently no information on small molecule modulators for GRAIL, TRAF and TRIM E3s, yet we anticipate such molecules to be developed soon due to highly promising nature of these enzymes as targets in cancer, inflammatory and autoimmune diseases. A novel paradigm-shifting approach that dramatically increases the attractiveness of RING-type E3 ligases as targets for drug design is based on proteolysis-targeting chimeras (PROTACs) [100,101]. These are hetero-bifunctional compounds with bivalent selectivity, they consist of three key elements: substrate-specific component (“warhead”), short linker, and E3-specific component. PROTACs bind and bring into close proximity substrate protein of interest and E3 ligase thus facilitating E3-mediated ubiquitination of the substrate. This approach, sometimes called as “chemical knockdown”, enables ligand-induced degradation of specific endogenous proteins [102]. Despite demonstrating high potential for a novel modality of chemical intervention on E3 ligases the use of PROTACs has yet unknown effect on modulation of immune response.
    Conclusions Inflammation and immune responses have evolved as a complex signaling architecture to resist a multitude of external and internal causes, such as infectious pathogens or autoimmunity. Recent advances in this field asserted ubiquitin-proteasome system as one of the cornerstones of this dynamic signaling framework. Accumulating evidence indicates that E3 ubiquitin ligases rise above other components of the UPS due to their expanding role in orchestrating a plethora of cell signaling outputs. These enzymes were proposed to become the “new kinases” owing to the significant therapeutic and market potential of their small molecule modulators [103]. E3s have indeed captured a significant attention of the research community because of their essential role in binding and poly-ubiquitinating target proteins.
    Conflict of interest