Neuropeptide engineering for improved chronic pain treatment

All human beings experience some kind of pain at some point in her/his life. Pain is a major health problem with an enormous impact on the individual and society. Pain can come in many forms (acute and chronic, mild, moderate and severe), and it is the most common cause for medical appointments. It is not only a disabling symptom of various medical conditions, but a disease state in its own right. Around 20-30% of all people worldwide suffer from chronic pain, and statistics show that pain is more prevalent than heart diseases or cancer. Today, effective pain control is a key factor in improving quality of life for pain patients. Opioids such as morphine are the most potent and effective analgesics for the treatment of severe and chronic pain, but they have poor efficacy against neuropathic pain. Their clinical use is largely limited by serious side effects including respiratory depression, sedation, constipation, tolerance and dependence liability. Opioid drugs produce analgesia but also adverse effects, by interaction with specific targets, the opioid receptors, present in the central nervous system and periphery. The current pharmacotherapy of chronic and neuropathic pain has proven to offer unsatisfactory solutions and stresses the need for alternative mechanism-based treatment strategies. This project comprises theoretical and experimental work undertaken in the field of opioid pharmacology and pain research, aiming to identify newly designed opioid drugs with reliable target-oriented pharmacology, efficacy, and safer use for the management of chronic pain conditions. The rationale of the project is based on the knowledge that natural ligands which modulate pain in humans are neuropeptides (endorphins, enkephalins, etc.). Without chemical modifications to provide enhanced stability and selectivity, neuropeptides are poorly suited for clinical applications. The innovative research avenue consists of the judicious engineering of neuropeptides to generate stable and selective peptide mimetics as novel analgesics with improved pharmacology and safety profiles. The strategy is based on the concept of multitarget ligands with a well-chosen activity and in which two active peptide pharmacophores are combined into one molecule. They can interact with multiple biological targets to induce a desired activity at each individual target, to prolong the analgesic activity and to provide more general painkillers active in acute, neuropathic and chronic pain. Drugs with such novel biological profiles will lead to medical benefits for the treatment of pain. Multidisciplinary, synergistic strategies based on innovative and highly efficient methods will be applied to achieve the goals of the research program, which includes drug design, synthesis, pharmacological experimental testing and molecular modeling. Future perspectives of this project are of major relevance due to the increasing number of chronic pain patients and the inadequate and toxicity of current therapies.

Pain, particularly severe and chronic pain, constitutes a major-public health problem with an enormous impact on both the individual and the society. While opioid-based pharmacotherapy is the most powerful strategy for the treatment of moderate to severe pain, the benefit/risk ratio is suboptimal due to multiple and severe adverse effects. The majority of clinically used opioids (e.g. morphine, oxycodone, fentanyl) bind and activate the -opioid receptor (MOR), which mediates beneficial (analgesia), but also non-beneficial effects. However, they also cause addiction and overdose deaths, which have led to a global opioid crisis during the past decades. The imperative need for effective, safer and nonaddictive pain therapies continues to drive the search for novel leads and new treatment strategies, with alternative chemical and pharmacological strategies being evaluated to mitigate the deleterious effects of opioids. This research project included computational and experimental work in the field of opioid drug discovery, opioid pharmacology and pain research, aiming to identify new, scientifically proven opioid drugs with reliable target-oriented pharmacology, efficacy, and safer use for the treatment of various pain conditions. The concept of 'one molecule, multiple targets - multifunctional/multitarget ligands' received increased attention over the past years as a promising approach for the discovery of effective and safer opioids, and it was of central attention in this project. Bifunctional ligands (peptides/peptidomimetics and small molecules) targeting the MOR simultaneously with other neurotransmitter (opioid/non-opioid) systems involved in pain processing and/or opioid-induced side effects were created as novel analgesics with improved pharmacology and safety profiles. Additionally, innovative formulation strategies targeting peptide-based hydrogels as promising delivery systems for controlled-release of opioid analgesics and discovery of new chemotypes as natural products via virtual screening are significant added-values to the project. Multidisciplinary and synergistic approaches were combined in this project to achieve the specific aims, ranging from the molecular in silico and in vitro levels to in vivo systems, with bioinformatics and computational systems and state-of-the-art biochemical, pharmacological and disease animal models, suitable to endow the investigations with high translational potential. Besides the scientific aspect, this project entails medical, social and economic perspectives in a long-term basis. One is to offer patient relief from incapacitating severe and chronic pain conditions, by introducing more efficient analgesic drugs with reduced side effects. The social aspect can be a decrease in sick-listing and early retirement because of chronic pain, which will reduce the social costs. Thus, more effective and well-tolerated pharmacotherapy may facilitate return to professional life and improve work performance. The economic aspect is to open up a new market within the pharmaceutical sector.