Isogenica, Biolauncher, Cresset Win Funds to Develop Small Molecule Drug Discovery Platform

It has been noted in around 20 percent of the world population suffers from some form of pain or the other. In many individuals, pain may be relieved initially with pain medications, but soon tolerance develops, and there is a decrease in the efficacy of pain relievers. One of the main symptoms of IBS seen commonly in many sufferers is chronic abdominal pain. Professor Lewis said, "All pains are complex, but gut pain is particularly challenging to treat and affects around 20 percent of the world's population. Current drugs are failing to produce effective pain relief in many patients before side effects limit the dose that can be administered." Professor Brierley echoed this statement saying, "Internal organs have a complex network of sensory nerves that have a wide array of voltage-gated ion channels and receptors to detect stimuli... The hypersensitivity of these nerves in disease often contributes to the development of pain."

The endogenous opioids and their receptors are widely distributed throughout the central and peripheral nervous systems, particularly the parts of these systems that regulate pain, emotion, reward, stress responses, motivation, drug addiction, and autonomic control. The differential expression and location of the various receptor subtypes across different neurons account for the wide range of opioid-related behaviors. The activation of µ-opioid receptors is mainly known for playing a role in pain relief. Still, research has also indicated it may be involved in behaviors related to survival, such as appetite and reproduction. The activity of µ-opioid receptors is also known to play a critical role in responses to social stimuli by modulating responses to social rejection or social acceptance, for example. Activation of the δ-opioid receptors and κ-opioid receptors is also known to be involved in pain modulation. Also, studies have shown that NOP activation is involved in pain mechanisms and several behaviors related to psychological stress. Alterations in the endogenous opioid system are suspected to be involved in Parkinson's disease, seizures, neuroprotective mechanisms, and depression.

Conventional pharmacological studies on spices have traditionally focused on secondary metabolites like polyphenols, alkaloids, and terpenes. More recently, food science research has also examined spice proteins and their enzymatic hydrolysates, using proteomic methods such as liquid chromatography–tandem mass spectrometry (LC-MS/MS) to identify short bioactive peptide sequences released from larger precursor proteins.6 Once released during food processing, fermentation, or gastrointestinal digestion, these functional peptides can act as metabolic regulators, antimicrobials, or antioxidants.1 Functional peptides refer to specific protein fragments that, once released from their parent proteins, exert biological activities.1,2 In the context of foods, these activities are most often demonstrated using in vitro biochemical or cell-based assays, and their physiological relevance depends on bioavailability and dose.2 Unlike intact proteins, which can have the potential to be allergenic or difficult to absorb due to their complex tertiary structures, functional peptides may exhibit improved bioaccessibility, and some small peptides can cross the intestinal epithelial barrier via peptide transport systems. However, absorption efficiency varies substantially by peptide sequence and digestive conditions.6 Nutriomics and mechanistic investigations have established that the bioactivity of a peptide is dictated by its physicochemical properties, particularly its amino acid composition, molecular weight, and net charge. For example, the presence of hydrophobic amino acids like proline, leucine, and valine often correlates with high antioxidant and enzyme-inhibitory activity.2,3 Smaller peptides, typically those less than three kilodaltons (kDa) in size, exhibit greater stability against proteolytic degradation in the gastrointestinal tract.3 Moreover, cationic peptides are particularly effective as antimicrobial agents through their electrostatic interactions with bacterial membranes.3

Adaptive immunity is the ability of specific lymphocytes to differentiate between self and non-self (foreign) antigens and defend the body by selectively destroying non-self-peptides. This concept is possibly the most crucial factor in several immunological medical domains and is increasingly being explored across cancer immunotherapy, vaccine design, pathogen identification, and autoimmune disorders (including allergies). A growing body of literature elucidates the importance of peptides, short amino acid chains linked via peptide bonds, in providing the adaptive immune system with the information required to effectively distinguish between self and non-self particles. This has resulted in the proposal of the ‘immune self’ concept, which postulates that self-similarity is a fundamental determinant of immune recognition. First introduced by Frank MacFarlane Burnet in 1949, the immune self-concept and its sister, the self-nonself theory, have substantially evolved over the decades. Initially driven by observations from Medawar’s early transplantation experiments, Nils K. Jerne (1974; eigen-behavior theory), Polly Matzinger (1994; danger theory), and most recently, evidence from research conducted independently by Waldmann, Mitchison, and Janeway has refined the immune self-concept from ‘all body elements are self, and foreign elements are non-self’ to the most recent ‘infectious non-self (foreign and usually harmful) versus noninfectious self (safe) elements.’

Some bacterial species produce antimicrobial peptides known as bacteriocins that have been used in the food industry as preservatives. For example, nisin, which is produced by Lactococcus lactis, has broad-spectrum bactericidal activity and has been used as a food preservative throughout the world. Nisin is effective in controlling Gram-positive bacteria such as Clostridioides difficile. In combination with other compounds like ethylene diamine tetra-acetic acid and cinnamaldehyde, nisin has been effective in controlling enterotoxigenic Gram-negative bacteria such as Escherichia coli. Previous studies have used chicken and mouse models to demonstrate the in vivo efficacy of nisin on the microbiome, whereas nisin efficacy has been proven in ex vivo experiments on the human microbiome. To date, no studies have assessed the in vivo effects of nisin in large mammals.