Historical Spice as a Future Drug: Therapeutic Potential of Piperlongumine

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferonγ(IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.

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Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

10.5772/intechopen.100534 ◽

2021 ◽

Author(s):

Julius Tieroyaare Dongdem ◽

Cletus Adiyaga Wezena

Keyword(s):

Therapeutic Potential ◽

Protein Complexes ◽

Ring Finger ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Phd Finger ◽

E3 Ligases ◽

Cellular Processes ◽

Future Drug ◽

Ubiquitin Conjugating Enzyme

E3 ubiquitin ligases of which there are >600 putative in humans, constitute a family of highly heterogeneous proteins and protein complexes that are the ultimate enzymes responsible for the recruitment of an ubiquitin loaded E2 ubiquitin-conjugating enzyme, recognise the appropriate protein substrate and directly or indirectly transfer the ubiquitin load onto the substrate. The aftermath of an E3 ligase activity is usually the formation of an isopeptide bond between the free carboxylate group of ubiquitin’s C-terminal Gly76 and an ε-amino group of the substrate’s Lys, even though non-canonical ubiquitylation on non-amine groups of target proteins have been observed. E3 ligases are grouped into four distinct families: HECT, RING-finger/U-box, RBR and PHD-finger. E3 ubiquitin ligases play critical roles in subcellular signalling cascades in eukaryotes. Dysfunctional E3 ubiquitin ligases therefore tend to inflict dramatic effects on human health and may result in the development of various diseases including Parkinson’s, Amyotrophic Lateral Sclerosis, Alzheimer’s, cancer, etc. Being regulators of numerous cellular processes, some E3 ubiquitin ligases have become potential targets for therapy. This chapter will present a comprehensive review of up-to-date findings in E3 ligases, their role in the pathology of disease and therapeutic potential for future drug development.

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Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

10.20944/preprints201912.0058.v1 ◽

2019 ◽

Author(s):

Zikai Feng ◽

Jason A. Smith ◽

Nuri Gueven ◽

Joselito P. Quirino

Keyword(s):

Therapeutic Potential ◽

Metabolic Stability ◽

Short Chain ◽

Side Chain ◽

Drug Candidates ◽

Metabolic Conversion ◽

Reversible Redox ◽

Future Drug ◽

Hepatocarcinoma Cells ◽

Phase Liquid

Short chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts is therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1-16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively.

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The Therapeutic Potential of Medicinal Foods

Advances in Pharmacological Sciences ◽

10.1155/2014/354264 ◽

2014 ◽

Vol 2014 ◽

pp. 1-18 ◽

Cited By ~ 16

Author(s):

Nelvana Ramalingum ◽

M. Fawzi Mahomoodally

Keyword(s):

Nutritive Value ◽

Therapeutic Potential ◽

Folk Medicine ◽

Scientific Data ◽

Food Plants ◽

Medicinal Foods ◽

Future Drug ◽

Pharmacologically Active

Pharmaceutical and nutritional sciences have recently witnessed a bloom in the scientific literature geared towards the use of food plants for their diversified health benefits and potential clinical applications. Health professionals now recognize that a synergism of drug therapy and nutrition might confer optimum outcomes in the fight against diseases. The prophylactic benefits of food plants are being investigated for potential use as novel medicinal remedies due to the presence of pharmacologically active compounds. Although the availability of scientific data is rapidly growing, there is still a paucity of updated compilation of data and concerns about the rationale of these health-foods still persist in the literature. This paper attempts to congregate the nutritional value, phytochemical composition, traditional uses,in vitroandin vivostudies of 10 common medicinal food plants used against chronic noncommunicable and infectious diseases. Food plants included were based on the criteria that they are consumed as a common food in a typical diet as either fruit or vegetable for their nutritive value but have also other parts which are in common use in folk medicine. The potential challenges of incorporating these medicinal foods in the diet which offers prospective opportunities for future drug development are also discussed.

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Therapeutic Potential of Peptides Derived from Animal Venoms: Current Views and Emerging Drugs for Diabetes

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.1177/11795514211006071 ◽

2021 ◽

Vol 14 ◽

pp. 117955142110060

Author(s):

Aimee Coulter-Parkhill ◽

Stephen McClean ◽

Victor A Gault ◽

Nigel Irwin

Keyword(s):

Drug Discovery ◽

Therapeutic Potential ◽

Cell Signalling ◽

Proof Of Concept ◽

Sea Anemones ◽

Gila Monster ◽

Future Drug ◽

Treatment Of Diabetes ◽

Human Use ◽

Animal Venoms

The therapeutic potential of venom-derived drugs is evident today. Currently, several significant drugs are FDA approved for human use that descend directly from animal venom products, with others having undergone, or progressing through, clinical trials. In addition, there is growing awareness of the important cosmeceutical application of venom-derived products. The success of venom-derived compounds is linked to their increased bioactivity, specificity and stability when compared to synthetically engineered compounds. This review highlights advancements in venom-derived compounds for the treatment of diabetes and related disorders. Exendin-4, originating from the saliva of Gila monster lizard, represents proof-of-concept for this drug discovery pathway in diabetes. More recent evidence emphasises the potential of venom-derived compounds from bees, cone snails, sea anemones, scorpions, snakes and spiders to effectively manage glycaemic control. Such compounds could represent exciting exploitable scaffolds for future drug discovery in diabetes, as well as providing tools to allow for a better understanding of cell signalling pathways linked to insulin secretion and metabolism.

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Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

Pharmaceuticals ◽

10.3390/ph13020029 ◽

2020 ◽

Vol 13 (2) ◽

pp. 29

Author(s):

Zikai Feng ◽

Jason A. Smith ◽

Nuri Gueven ◽

Joselito P. Quirino

Keyword(s):

Therapeutic Potential ◽

Metabolic Stability ◽

Short Chain ◽

Side Chain ◽

Drug Candidates ◽

Metabolic Conversion ◽

Reversible Redox ◽

Future Drug ◽

Hepatocarcinoma Cells ◽

Phase Liquid

Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts its therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1–16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively.

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Novel protein–inhibitor interactions in site 3 of Ca2+-bound S100B as discovered by X-ray crystallography

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798316005532 ◽

2016 ◽

Vol 72 (6) ◽

pp. 753-760 ◽

Cited By ~ 6

Author(s):

Michael C. Cavalier ◽

Zephan Melville ◽

Ehson Aligholizadeh ◽

E. Prabhu Raman ◽

Wenbo Yu ◽

...

Keyword(s):

Therapeutic Potential ◽

Structural Data ◽

Protein Inhibitor ◽

Design Studies ◽

X Ray ◽

X Ray Crystallography ◽

Cell Assays ◽

Future Drug ◽

Hydrophobic Cleft ◽

Novel Protein

Structure-based drug discovery is under way to identify and develop small-molecule S100B inhibitors (SBiXs). Such inhibitors have therapeutic potential for treating malignant melanoma, since high levels of S100B downregulate wild-type p53 tumor suppressor function in this cancer. Computational and X-ray crystallographic studies of two S100B–SBiX complexes are described, and both compounds (apomorphine hydrochloride and ethidium bromide) occupy an area of the S100B hydrophobic cleft which is termed site 3. These data also reveal novel protein–inhibitor interactions which can be used in future drug-design studies to improve SBiX affinity and specificity. Of particular interest, apomorphine hydrochloride showed S100B-dependent killing in melanoma cell assays, although the efficacy exceeds its affinity for S100B and implicates possible off-target contributions. Because there are no structural data available for compounds occupying site 3 alone, these studies contribute towards the structure-based approach to targeting S100B by including interactions with residues in site 3 of S100B.

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Discovery of multiple hidden allosteric sites by combining Markov state models and experiments

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1417811112 ◽

2015 ◽

Vol 112 (9) ◽

pp. 2734-2739 ◽

Cited By ~ 111

Author(s):

Gregory R. Bowman ◽

Eric R. Bolin ◽

Kathryn M. Hart ◽

Brendan C. Maguire ◽

Susan Marqusee

Keyword(s):

Drug Design ◽

Therapeutic Potential ◽

Rational Drug Design ◽

Markov State ◽

Markov State Models ◽

Starting Point ◽

Allosteric Sites ◽

Future Drug ◽

State Models ◽

Markov State Modeling

The discovery of drug-like molecules that bind pockets in proteins that are not present in crystallographic structures yet exert allosteric control over activity has generated great interest in designing pharmaceuticals that exploit allosteric effects. However, there have only been a small number of successes, so the therapeutic potential of these pockets—called hidden allosteric sites—remains unclear. One challenge for assessing their utility is that rational drug design approaches require foreknowledge of the target site, but most hidden allosteric sites are only discovered when a small molecule is found to stabilize them. We present a means of decoupling the identification of hidden allosteric sites from the discovery of drugs that bind them by drawing on new developments in Markov state modeling that provide unprecedented access to microsecond- to millisecond-timescale fluctuations of a protein’s structure. Visualizing these fluctuations allows us to identify potential hidden allosteric sites, which we then test via thiol labeling experiments. Application of these methods reveals multiple hidden allosteric sites in an important antibiotic target—TEM-1 β-lactamase. This result supports the hypothesis that there are many as yet undiscovered hidden allosteric sites and suggests our methodology can identify such sites, providing a starting point for future drug design efforts. More generally, our results demonstrate the power of using Markov state models to guide experiments.

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