# Targeting the Melanocortin 1 Receptor by Selective Small Analogs of α-Melanocortin for Melanoma Prevention

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2022 · —

## Abstract

Solar ultraviolet radiation (UV) is the main etiological factor for melanoma, the deadliest form of skin cancer,
and the fifth most diagnosed cancer in veterans. The incidence of melanoma is higher in veterans than in
civilians, particularly in individuals with light skin color and poor tanning ability. Over 65% of all veterans have
this phenotype. Deployment of millions of soldiers in geographical areas such as Iraq and Afghanistan
increases their risk for melanoma due to unavoidable daily excessive sun exposure without optimal protection.
Given the limitations of advanced therapeutic options for melanoma, it is important to focus on developing new
chemoprevention strategies to reduce its incidence. Our goal is to develop a melanoma prevention strategy
based on targeting the melanocortin 1 receptor (MC1R), the product of a bona fide melanoma predisposition
gene known to be a major regulator of human pigmentation and the response of melanocytes to solar UV. We
were the first to report the seminal findings that activation of the MC1R, a membrane-bound Gs protein-coupled
receptor expressed on melanocytes, by its agonist α-melanocyte stimulating hormone (α-melanocortin; α-MSH)
reduces UV-induced DNA damage by enhancing DNA repair and antioxidant capacities, in addition to
stimulating the synthesis of photoprotective eumelanin. Others have shown that expression of a loss-of-
function variant of MC1R is associated with increased UV signature mutations and the common somatic
V600E mutation in BRAF, that drive melanomagenesis. About 50% of all White Caucasians, including about 7
million veterans, are heterozygous carriers of a MC1R variant, a genotype associated with increased risk for
melanoma. These individuals will particularly benefit from our prevention strategy that will enhance the
activation of the MC1R. We have developed tetra- and tripeptide analogs of α-MSH that mimic the effects of
α-MSH on human melanocytes, and are stable and lipophilic, and unique in their high selectivity for the
MC1R. The cosmetic use of these peptides is covered by a published patent application. The tetrapeptides are
100 fold more potent, and the tripeptides are only 10 fold less potent than α-MSH in activating MC1R signaling
and its downstream effects in cultured human melanocytes. These peptides enhanced repair of UV-induced
DNA photoproducts, and increased pigmentation of cultured human skin substitutes (CSS) without any UV
exposure. These small peptides, unlike α-MSH, should not cause immunosuppression, since they lack
the COOH-terminal 11-13 amino acid residues (Lys-Pro-Val) of α-MSH that are responsible for its anti-
inflammatory and immunosuppressive effects. We propose that our tri- and tetrapeptide analogs of α-MSH
that are selective for the MC1R will be developed as topical agents to stimulate skin pigmentation and reduce
UV-induced DNA damage, in order to maintain the genomic stability of melanocytes, and therefore reduce the
risk for melanoma in veterans. ...

## Key facts

- **NIH application ID:** 10474302
- **Project number:** 5I01BX003668-05
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** ZALFA ABDEL-MALEK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474302

## Citation

> US National Institutes of Health, RePORTER application 10474302, Targeting the Melanocortin 1 Receptor by Selective Small Analogs of α-Melanocortin for Melanoma Prevention (5I01BX003668-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10474302. Licensed CC0.

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