Melanocortin: It’s Not Just For Lizards Any More

If you’re looking for a good example of evolution-as-a-tinkerer, the melanocortin receptors would be a good place to start. From a single starting point, they’ve ended up as a family of related proteins that do completely different things. And the hormones that bind to them have radiated out as well: they’re all derived by processing of a common precursor, pro-opiomelanocortin (POMC), and the first big split was the differentiated function of two of those cleavage products into what we would now call adrenocorticotrophic hormone (ACTH) and melanocyte-stimulating hormone (MSH). By now, humans have three forms of the latter (alpha, beta, and gamma MSH), and the receptor proteins have branched into five different MCxR subtypes as well. (Evolutionary molecular biology puts a lot of this back into roughly the lamprey/lungfish stage of things – the splits seem to have developed though gene duplication events during the periods of jawed fish and tetrapod evolution).

Along the way, they’ve each landed in their own niches. MC1R is the receptor signaling mechanism for melanin production, and is activated by MSH. The MC3R, MC4R, and MC5R receptors also respond to the different MSH subtypes in varying degrees, and these regulate things like (among others) hunger/satiety, immune response, sexual arousal, and sebaceous gland secretion – a bizarre collection indeed, which is exactly what you get after a billion years of “Hey man, whatever works”. Adding to the fun are the endogenous agouti peptides, which seem to be inverse agonists of the receptors and make their signaling ever more complex. Those have the same splits in function – agouti-signaling peptide was discovered through its effects on coat color in animals, while agouti-related peptide is a potent appetite stimulant.

This makes for quite a selectivity problem if you’re going to try to develop drugs in this area. A number of compounds have been worked on over the years, but not much has made it through, despite the marketing potential of a drug combination that could simultaneously make you lose weight, increase your sexual appetite, and give you a tan. That last one sounds fairly trivial, but it’s the target of a marketed drug, Scenesse (afamelanotide), which is a modified synthetic version of MSH. It’s administered by subcutaneous implant to people with skin pigmentation disorders, but it’s not very selective at all. Side effects (nausea, headache, decreased appetite, etc.) are quite noticeable, and since you’ve been dosed with a two-month supply, there’s not much to be done about them. (Update: I should also note bremelanotide, another MSH-like peptide with a very long and convoluted history in the clinic, which is currently heading to the FDA for a controversial female sexual dysfunction indication).

So here’s a new paper on efforts to develop a more selective MSH peptide from the same group at Arizona that discovered afamelanotide. They’d found a candidate in their earlier work, but it had several noncanonical amino acids, which slowed down potential development. The new paper is an attempt to replicate (or better) that selectivity while only using standard amino acids – in other words, to improve on nature directly. And so far, this looks possible: their new species has better selectivity than endogenous MSH, and a longer half-life in human plasma (MSH’s is five minutes, afamelanotide’s is 30 minutes, and the new species is 17 minutes).

And it certainly does the job on MC1R. Shown is an experiment on a green anole lizard (their color-changing abilities mean that they have a lot of melanocytes in their skin). Injection of afamelanotide, as shown, turns the lizard black within sixty seconds, an effect that takes two weeks to completely wear off (no doubt to the lizard’s consternation). The new peptide has exactly the same effect, but the lizard is back to his green self within 24 hours.I have to say that while I’ve had compounds go into all sorts of animal models in my career, the Ninja Lizard assay is a new one on me. The compound is still only a partial agonist (54% of maximum effect in the cell assays), but that certainly seems to be good enough, and it’s 16-fold selective for the MC1R subtype.

So this looks like a promising candidate for a second-generation therapy. If it’s safe enough, the hope is that such a drug could move into a broader market protecting people who at are higher risk for melanoma, since darkening the skin without having to expose people to lots of UV to start with would be an ideal way to accomplish that. I’ll leave the sociological implications to others, noting only that suntans themselves have moved over the years in the Western countries from a sign of being a fieldhand, to a sign of being wealthy and leisured, to a sign (in excessive cases) of spending too much money on tanning beds and body sprays. Anole lizards no doubt have their own take.

Source link


Leave a Reply

Your email address will not be published. Required fields are marked *