Interleukin-17 (IL-17) is a family of 6 closely related cytokines, designated IL-17A-F, that play a central role in mediating inflammation, autoimmunity, and host defense. IL-17 is mainly secreted by a specific subset of T helper cells known as TH17 cells (for an overview see Fig 1). The IL-17 cytokines mediate their biological functions via surface receptors on target cells. IL-17A binds to IL-17 receptor A (IL-17RA), which stimulates the production of other pro-inflammatory cytokines including IL-6 and IL-8. IL-17A and its receptor play a pathogenic role in many inflammatory and autoimmune diseases such as rheumatoid arthritis. IL-17 signaling is also involved in mucosal immunity and host defense against extracellular bacterial and fungal infections (Staph, Candida, Pneumonia, etc.). [Read more…]
Trpytophan (trp) is an important and essential amino acid that has a variety of functions within the cell. In addition to being incorporated into the polypeptide chain of proteins, various catabolic pathways can produce a number of functional Trp derivatives. Trp is the biosynthetic precursor of the co-factor NAD, a number of antibiotics, and the neurotransmitters serotonin and melatonin.
The factors regulating the fate of Trp in the cell have yet to be fully elucidated, but likely involve specific enzymes that may vary in expression levels or with the cell type (Fig 1 – Shown is a depiction of two important tryptophan catabolic pathways and the enzymes that participate in the process). [Read more…]
A ready-to-use E3 ligase activity enzymatic assay, the E3LITE kit, has been recently designed enabling researchers to screen for E3 enzyme inhibitors and potentially new therapeutical drugs. What’s it for and why is it of interest?
While it is likely that all Ubiquitin-Like proteins (UBLs) will be important for drug discovery because of these associations, Ubiquitin has been the most completely validated for this purpose by genetic, biological, and biochemical evidence. The enzymes of the Ubiquitin pathway are emerging as pioneer drug targets for many therapeutic areas.
The ubiquitin family of proteins is an important means of regulating protein trafficking, cell division, apoptosis, and metabolism in cells. Turnover of most cellular proteins is effected by ubiquitin tagging, which marks them for transport to the 26S proteasome for degradation. [Read more…]
In a recent post, I concentrated on the role of HDACs in cancer: Histone Deacetylases (HDACs) and Cancer and mentioned that some HDACs are overexpressed and show very high activities in a number of tumours. Today, I ‘ll focus on the role of HDACs in Alzheimer’s disease, which accounts for 60 to 70% of dementia cases. Taking into account the demographic development – it has been projected that by 2050, people aged 60 and over will account for 22% of the world’s population – and the fact that it affects approx. 6% of people older than 65 years, the WHO stated that “Alzheimer disease (AD) has become a major public health concern…” (Background Paper 6.11; 2013). [Read more…]
Histone Methyltransferases (ex. EZH1 and EZH2, and G9a) and their counter-parts (Histone demethylases like JARID1, the KDM4, and the JMJD family) have become promising targets for inhibitor screenings, especially in Cancer drug discovery. (1, 2) Accessing a wide variety of pure and well-characterized bioactive small molecules is of importance when characterizing these enzymes.
Here, we’ve compiled a list of 19 bioactive compounds currently seen in the literature when studying Histone Methyltransferases and Demethylases in Drug Discovery. [Read more…]
The treatment of diseases by inducing, enhancing, or surpressing an immune response is referred to as Immunotherapy. T-cell activation and inactivation requires the coordination of various co-inhibitory and co-stimulatory signals and most immunotherapies modulate these signals.
Therapeutic manipulation of immunopathways has lead to promising clinical results for the treatment of a number of diseases such as cancer, autoimmune diseases and inflammatory diseases. Research in this field is rapidly evolving as scientists seek to identify the next generation of therapies.
Over the past 12 months I have introduced a number of pathways and proteins involved, which represent potential targets for drug discovery campaigns and I’ve presented assays to measure inhibitor effects on these pathways (B7-1 / CD28 and B7-1 / CTLA4; PD-1/PD-L1/PD-L2; BLTA:HVEM, CD47:SIRPα; GITR:GITRL; CD40:CD40L; CD137:CD137L; IDO).
Histon Deactetylases (HDACs) are overexpressed and show very high activities in a number of tumor cells. Expression of HDAC1, -5, and -7 can be even used as a cancer biomarker. Moreover, they play a crucial role in oncogene expression.
HDACs remove acetyl groups from N acetyl lysine residues in histones. These enzymes belong to a number of enzymes which control the condensation status of nucleosomes (structure of a mono nucleosome is shown in Fig.1). While acetylation of histones by Histone acetyltransferases leads to decondensation and thus allows DNA binding proteins to interact with exposed sites to activate gene transcription, the activity of HDACs allows histones to wrap the DNA more tightly.