The body consists of cells which communicate with each other via signaling molecules to govern and determine a variety of physiological functions in the body. The action and effect of these signaling molecules is mediated by ‘receptors’ which are located on the surface of (plasma membrane), or inside a cell. A molecule that ‘binds’ with a receptor is known as a ligand and can be protein such as a hormone or drug and the role of the ligand is to activate, or inactivate a particular biological activity.
In some ways receptors can be likened to switches with on and off positions, and which in turn affect the cell’s internal functioning. The action or inaction of receptors is determined by the type of ligand with which they bind, i.e. receptors are activated when an agonising ligand, an ‘agonist’ binds and left inactive when an ‘antagonist’ in some way prevents the agonist from binding. The specific biological action is dependent upon which particular ligand binds with a receptor.
An activated or agonised receptor has many effects ‘downstream’ – elsewhere in the body – as it triggers a cascade of further reactions. For example; selective α-MSH agonists bind with melanocortin receptor type 1 located on the surface of melanocytes, instigating a chain reaction which eventuates in change in the chemical balance within melanocytes and favours the production of eumelanin.
Specifically within Clinuvel’s field of expertise and interest falls the melanocortin (MC) system. This consists of MC agonists including α, β and γ –MSH, ACTH (adrenocorticotropic hormone), antagonists such as agouti and AGRP (agouti related protein) and the five identified MC receptors (MC1R – MC5R). This system is highly complex and has been implicated in a wide range of physiological processes, among them pigmentation, inflammation, sexual function, energy homeostasis and appetite, among others.
The biological effects of MC are mediated by the activation of the receptors which differ from each other widely in terms of their tissue distribution and binding affinities (strengths) of the various agonists and antagonists.
This system is genuinely fascinating; from the history of its exploration and discovery, through the wide-ranging and varied physiological actions within its influence. Fundamental to the MC system is proopiomelanocortin (POMC), the common precursor protein from which the MC are cleaved. POMC has been identified in various species of mammals, amphibians and teleosts. In fact, the most ancient vertebrate, the marine lamprey, has a POMC sequence with similar structure, implying that the POMC sequence is itself in excess of 700 million years old.
Also of interest are the wide ranging, and surprising physiological responses that the broader non-selective MC system influences. The therapeutic potential of influencing appetite, energy or pigmentation and inflammation are obvious, but the unlooked for and startling activation of an excessive grooming response or SYS (stretching yawning syndrome) marked the initial discovery that the MC had an extra-hormonal effect on the brain, making MC the first class of ‘neuropeptides’, discovered more than half a century ago.
Complicating the delivery of therapeutic benefit is the variety of areas that different receptors, agonists and antagonists are expressed. The wide distribution of these receptors means the intent to instigate a beneficial process in one area could result in a detrimental process in a seemingly unrelated or physically distant area. For this reason development of the melanocortin ligands has necessarily involved amendments to their structure to improve binding affinity, create a more selective agonist and/or increase the half life, allowing a more sustained or controlled physiological response.
Alongside this are the administration, or drug delivery avenues that are being explored, as intravenous or subcutaneous injection, nasal spray, oral or topical formulations can deliver varying amounts of drug to different pockets of receptors and with varying results and downstream effects. Perfecting the release profile of a ligand drug product is fundamental to achieving a therapeutic result and mitigating unlooked for or unexpected downstream effects. Ultimately the goal is the development of MC analogues that have targeted and desirable biological activity.
Clinuvel today finds itself in an incomparable and individual position. Our expertise and progress to date define us as uniquely innovative in the field of medicinal photoprotection, alone in our focus on afamelanotide (an α-MSH derivative) as a selective MC1R agonist and our application of therapeutic benefit for unique, light and UV related disorders.
References:
http://www.ncbi.nlm.nih.gov/pubmed/14535656
http://www.ncbi.nlm.nih.gov/pubmed/18996199
http://www.ncbi.nlm.nih.gov/pubmed/16293341
http://www.ncbi.nlm.nih.gov/pubmed/16412534
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