Enhanced melanoma cancer prevention by novel melanotropins (arizona board of regents on behalf of university of arizona) side effects of hormonal imbalance

There is a critical medical need for prevention of skin damage and development of melanoma and other cancer cells in the human skin caused by ultraviolet (UV) chemical damage to DNA in the cell. Skin cancer is the most commonly diagnosed cancer in the US, and an estimated 76,380 new cases of melanoma will be diagnosed in the US in 2016. Current efforts to prevent UV damage to human skin, which in many cases leads to melanoma and other skin cancers, is primarily limited to using lotions containing organic compounds that absorb light in the UV absorption regions of the electromagnetic spectrum (200-800 nM). Although this approach has some success, the use of lotions is an overall failure due to the inadequacies of the lotions or the improper or inadequate use of these lotions. It has been observed that when dark- and light-skinned persons both spend significant time in the sun, dark-skinned persons have a much lower risk of developing melanoma.


Internally simulated photo-protection of human skin would provide a more effective path to sun protection and cancer prevention than currently available via sunscreen lotions.

Melanocyte stimulation hormones (MSH), also known as melanotropins, are products of the natural precursor protein, propiomelanocortin (POMC), which is found in all terrestrial animal life and is responsible for both skin and hair color in animal life. MSH consists of αa-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating hormone (β-MSH), and γ-melanocyte-stimulating hormone (γ-MSH). The melanocortin 1 receptor (MC1R), also known as a melanocyte-stimulating hormone receptor, a melanin-activating peptide receptor, or a melanotropin receptor, is a protein that can bind to MSH, and is known to regulate pigmentation for the skin. When MC1R is activated, it can trigger melanocytes to produce eumelanin, which is a type of melanin that can protect the skin from damage caused by UV radiation in sunlight. The γ-MSH is one of a family of naturally occurring peptide hormones that are released by skin cells in response to the damaging rays of UVR. Because γ-MSH has higher affinity for MC1R, while showing less affinity for MC3R, MC4R, and MC5R receptors, it almost exclusively induces melanin production. As it is more selective for MC1R, γ-MSH can have less negative side effects than the other family members, α-MSH and β-MSH.

The present invention features organic peptides related to the melanocyte stimulation hormone. These compounds are the most selective for the relevant hMC1R. The target peptide γ-MSH is modified to improve its properties as a cancer preventive to make γ-MSH more stable, more MCR1 selective, and more readily bioavailable for topical or transdermal delivery.

Studies have shown that “skin tanning (pigmentation)” by the native hormone α-MSH and especially by a more stable analogue [Nle4, D-Phe7] α-MSH (NDP-α-MSH) protects against UV damage to the skin of normal humans, including those who do not pigment well in response to UV radiation (UVR). Hence, the present invention provides an innovative approach to promote the natural pigmentation of skin without exposure to sunlight with a peptide ligand that is selective for the hMC1R and therefore will have no side effects (toxicities). Moreover, because the present invention internally stimulates photo-protection of human skin, it provides a more effective path to UVR protection and cancer prevention than the protection currently available from commercial chemical sunscreens (lotions, sprays, etc.) and it does not rely on multi or daily reapplications.

Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims. SUMMARY

It is an objective of the present invention to provide for analogues of γ-MSH that are more stable, more selective for the melanocortin-1 receptor (MC1R), and more bioavailable, as specified in the independent claims. Embodiments of the invention are given in the dependent claims. Embodiments of the present invention can be freely combined with each other if they are not mutually exclusive.

In one embodiment, the subject disclosure features a modified melanocortin 1 receptor (MC1R) peptide ligand comprising naturally occurring amino acids, the MC1R peptide ligand being a derivative of γ-MSH. According to one embodiment, the MC1R peptide ligand can be according to SEQ ID NO. 1: