The melanocortin system involves numerous physiological functions and is associated with many diseases such as skin cancer, obesity and diabetes, sexual dysfunction and neuropathic pain among others. The design of selective, potent melanotropins has great potential for novel drug discovery. Traditionally, optimizing the interaction of lead molecules with the binding site of the endogenous agonist (the orthosteric site) has been viewed as the best means of achieving selectivity of action. However, our studies have highlighted the fact that novel designed melanotropins can interact with binding sites on the receptor molecule that are distinct from the orthosteric binding sites, known as allosteric binding. AUosteric binding could offer several advantages over orthosteric melanotropins, including greater selectivity as well as selective cell signaling. Here, we introduce a series of selective allosteric antagonists of melanotropins with distinct cell signaling compared to the conventional melanotropin activation.
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