RIPK1 inhibitions is a strategy proposed to block both necroptosis and apoptosis involvement in neurological or inflammatory diseases.
How might seemingly contradictory targets be reconciled in herbal bimolecular initiation of apoptosis as therapy for disease such as against malaria and cancer (e.g. Artemisia + Gardenia) and simultaneously blocking upstream necroptosis in sepsis and inflammatory disease?
What scope exists with seemingly intractable diseases? For example hepatic diseases such as cholangitis has high morbidity that lacks pharmacotherapy and etiopathogenesis to guide critically needed novel therapies (1). What insights does molecular biology of traditional ethno medicine offer clues to shorten lead times in researching and developing novel therapies, both pharmaceutical and in combination herbal formulations?
Some evidence suggest leaky gut and intestinal microflora, lifestyle, environment may partially explain Etiology of metabolic diseases. Some 90% of Primary Sclerosing Cholangitis (PSC) have been related to acquired environmental factors(1), immune dysregulation (2), as well reduced number of T-regulatory cells in inflamed hepato-biliary tissues (3).
Given terpinoids or perhaps a combination of so far undiscovered organic molecules within herbal ethno medicines such as Sophora sub-prostrata or Artemisia species may help balance CD4+ and CD8+ regulatory T cells, what scope exists for these in treating PSC, other forms of cholangitis, disease generally, including cancer?
To progress the field, what scope exists for modelling gene targets of mixed herbal formulations to advance our rich ethnomedical traditions toward new drug or herbal formulations in treating and preventing disease?
Thank you for sharing your expert and interesting and challenging question.
Dear Bernhard, Here I wanted to mention the Ophiopogonin D (OP-D), as organic natural product, it is a steroidal glycoside isolated from the traditional Chinese herbal agent Radix Ophiopogon japonicus (Mai Dong), has a significant protective effect on the cardiovascular system because of its pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-apoptotic effects.
OP-D can increase CYP2J2 and 11, 12-EET production, plays a protective role as an effective anti-inflammatory.
OPD`was shown to exert potent anti-tumor activity.
It induced apoptosis via a RIPK1-related pathway, increased the protein expression levels of RIPK1 and Bim, and decreased the levels of cleaved-RIPK1, caspase 8, cleaved-caspase 8, Bid, caspase 10, and cleaved-caspase 10.
OPD` also increased the mRNA expression of Bim.
The protein expression of Bim was decreased when cells were pre-treated with necrostatin-1.
RIPK1 has become an important drug target in the pharmaceutical industry not only due to its key roles in TNF signaling responses but also because the kinase structure of RIPK1 is highly amenable for developing specific pharmacological small-molecule inhibitors.
a novel kinase inhibitor chemotype is identified from a DNA-encoded library with high in vitro RIP1 potency and kinase selectivity. The lead optimization focused on improving the pharmacokinetic and developability profile of the series. SAR studies is revealed that replacement the isoxazole with a triazole was key to improving solubility, lipophilicity, and rat oral exposure, leading to the identification of the RIP1 clinical candidate.
Benzoxazepinone has excellent activity in both RIP1 cellular systems, preventing TNF induced necrotic cell death, and an ulcerative colitis explant assay blocking spontaneous cytokine release. The compound has highly favorable physicochemical and pharmacokinetic properties, which combined with high potency lead to a predicted once daily low dose in humans. Benzoxazepinone was advanced into phase 1 clinical trials in 2015, and phase 2a clinical trials in psoriasis, rheumatoid arthritis, and ulcerative colitis patients are currently underway.
Dear Pardis, thank you for your interesting contribution. Exactly the kind of activity, simultaneously pro and anti-apoptotic, perhaps contexts & settings dependant. Illuminating, targets, and to ask why such seeming duplicity! The kinase inhibitors amenable to chemical alteration, and activity thereof also, in context of their multiple roles. I'm always amazed at the diversity of small molecule variation in eukaryotes, form an multicellular evolutionary and developmental standpoint. Small metabolite diversity is normally the precinct of bacteria, albeit in different groups. But here we have diversity in subtle changes care off of eukaryotic genetic regulation complexity. Another interesting point is the intersect of these small molecules in regulating the energy budget of mitochondria. On the one hand oxidant/antioxidant modulation to control “bleed” overcapacity of the mitochondrial energy regime and on the other usefully linked gained intermediates molecular synthesis and feedback control. Simple aspirin is a case in mind mitochondria energy modulation, and in this respect monitoring the mitochondrial energy budget through markers appears to me a plausible avenue of research in adding potential diagnostic marker utility in treating and monitoring disease. Fascination times and opportunities for organic chemists like yourself to tweak these small molecules and team with pharmaceutical research. Thanks gain for your contribution, Kind regards, Bernie
You’re most welcome Dear Bernhard, yes it’s very interesting topic to discuss.
Protein kinases are among the most explored protein drug targets. Visualization of kinase conformations is critical for understanding structure–function relationship in this family and for developing chemically unique, conformation-specific small molecule drugs.
Also Selective protein kinase inhibitors are highly sought after as tools for studying cellular signal transduction cascades, yet few have been discovered due to the highly conserved fold of kinase catalytic domains.
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