Unlike other receptors within the TNFSF, BAFFR contains a single CRD, which interacts extensively with one monomer of BAFF

Unlike other receptors within the TNFSF, BAFFR contains a single CRD, which interacts extensively with one monomer of BAFF. be pursued for clinical development, they provide proof-of-principle evidence that these interactions are susceptible to small-molecule modulation and can serve as starting points toward the identification of more potent and selective candidates. C directly interfering with critical hot spots on the interface and competing with the original protein ligand; or C binding at some different site, but causing conformational changes that are sufficient to interfere with the binding of the protein ligand [6]. Most PPI modulators are PPI inhibitors (antagonists) and not agonists that enhance binding or stimulate SB-242235 activity; however, a few examples of agonists do exist. As mentioned [42], by all accounts, identification of small-molecule PPI stimulators is even more challenging than that of PPI inhibitors since they, in addition to binding, also need to trigger the downstream activation cascade [43]. Only a very limited number of small-molecule PPI agonists (i.e., enhancers or stabilizers) have been identified. Direct evidence of PPI stabilization is demonstrated by tacrolimus (FK506) and sirolimus (rapamycin) [44, 45]. In their absence, the immunophilin protein FKBP12 is unable to bind calcineurin and mTOR. However, these compounds can bind FKBP12 and then form a complex with calcineurin and mTOR, respectively [46C48]. Another example of PPI agonist is represented by the adenylyl cyclase (AC) binding forskolin [43]. Some other examples of stabilizers have been found for PPIs in which protein 14-3-3 is involved [49C51] and a possible small-molecule activator of TRAIL receptor DR5 that will be discussed later [52]. Here, we will review small-molecule modulators targeting PPIs within the TNF superfamily, which contains a large number of cell surface protein receptor-ligand interactions that represent highly valuable therapeutic targets. For TNFSF PPIs where small-molecule modulators have been published, a brief review of relevant structural and signaling aspects will be included with the description of the modulators. 2 TNF SUPERFAMILY The tumor necrosis factor (TNF) superfamily (TNFSF) contains about thirty structurally related receptors (TNFSF-R) and about twenty protein ligands that bind to one or more of these receptors [53C58]. TNFSF ligands are soluble or membrane-anchored trimers that cluster their cell surface receptors Rabbit Polyclonal to OR10Z1 to initiate signal transduction; a set of representative ligand-receptor interacting trimer structures obtained from corresponding crystal structures are shown for illustration in Figure 1. These interactions are integral to communication and signaling systems involved in numerous physiological functions essential to inflammatory signaling, to the functioning of the immune and nervous system, to bone development, and others. The development of protein-based biologics SB-242235 inhibiting the binding of TNF to its receptors, which have been shown to be effective in reducing the inflammation associated with several autoimmune diseases and have become some of the best selling drugs, is one of the few recent immunopharmacology success stories [59]. Following this success, considerable attention has been focused on the therapeutic potential of modulating other TNFSF interactions, and there are biologics in clinical development for almost all of these interaction pairs [57, 58]. Currently, there are five biologics blocking TNF (TNFSF2) or LT (TNFSF1) that are approved for treating various autoimmune and inflammatory disorders including rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, ankylosing spondylitis, Crohns disease and ulcerative colitis: etanercept (LT, TNFSF1 and TNF, TNFSF2), infliximab, adalimumab, certolizumab pegol, and golimumab (TNF, TNFSF2). There are also biologics targeting other TNFSF members approved for clinical use: brentuximab vedotin (CD30L, TNFSF8) for Hodgkins lymphoma and systemic anaplastic large cell lymphoma (sALCL); denosumab (RANKL, TNFSF11) for osteoporosis, and belimumab SB-242235 (BAFF, TNFSF13B) for systemic lupus erythematosus (SLE) and RA [58]. Open in a separate window Figure 1 Three-dimensional structures showing the interacting trimeric structures for human CD40CCD40L, TRAILCDR5, and OX40COX40L from two different perspectives C a side view (top row) and a 90-rotated top view (bottom row). Ribbon rendering of crystal structures are shown for PDB IDs 3QD6, 1D4V, and 2HEV, respectively with the ligands shown in reddish and the receptors shown in blueish colors. The crystal structure of.

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