Change a peptide ring by a few atoms and the same molecule stops blocking the body's main appetite switch and starts turning it on.
That is the result in a new paper in the Journal of Medicinal Chemistry ↗, where chemists built 14 ring-shaped peptides, between 19 and 23 atoms around, and tested each one against the four human melanocortin receptors. These receptors, labeled MC1R through MC5R, are close cousins that sit on different tissues and do very different jobs. MC1R sets skin pigment. MC4R, acting in the brain, governs hunger and sexual response. MC3R helps tune energy balance, and MC5R sits on the sebaceous and other exocrine glands. The trouble with drugging any one of them is that a molecule shaped to fit one tends to fit the others too, and the off-target hits are not subtle.
The three scaffolds the team started from make the point. Two are the research compounds SHU-9119 and PG-901; the third is melanotan II ↗, the gray-market "tanning peptide" that people inject to darken their skin. It darkens skin because it hits MC1R, and it drives the sexual-arousal and nausea effects melanotan II is known for by hitting MC4R. That is what a non-selective melanocortin drug looks like. It does several things at once because it cannot tell the receptors apart.
From that messy starting point, ring size did the sorting. Two of the new macrocycles, named FM648 and FM636, came out as potent and selective blockers of the MC4R receptor ↗, shutting it down while largely ignoring MC1R, MC3R, and MC5R. A third, FM635, did the opposite on the same receptor, switching it on with the same selectivity. One small family of rings, tuned by circumference, produced both an off switch and an on switch for the appetite receptor, without the skin-pigment and gland effects that sink the broad agonists.
Both directions have a real target. An MC4R agonist suppresses appetite, which is the mechanism behind setmelanotide ↗, sold as Imcivree for rare genetic obesity and built squarely around switching this receptor on. An MC4R antagonist does the reverse, and blockers are of interest for cachexia, the muscle-and-appetite wasting that hollows out cancer and advanced kidney patients. The two scaffolds from one lab map onto two different unmet needs.
The authors call macrocyclic peptides a "Goldilocks" class, bigger than a conventional pill and smaller than an antibody, which is the same pitch that put bremelanotide ↗, the female-desire drug Vyleesi, and setmelanotide on the market. Both are macrocyclic peptides aimed at melanocortin receptors. What this paper adds is a recipe for steering that class toward one receptor out of four, and toward either function, by editing the ring rather than rebuilding the molecule.
This is bench pharmacology, receptor and binding assays, not an animal study or a trial. None of FM648, FM636, or FM635 is a drug. But the finding names something useful for anyone designing the next melanocortin compound. Selectivity and direction are dials on the ring, not properties you are stuck with.