Zusammenfassung
Melanokortine sind Peptide, die sich chemisch durch ein gemeinsames zentrales Pharmakophor auszeichnen. Physiologisch steuern die natürlichen Melanokortine die Farbe von Haut und Haaren und regulieren zudem die Ultraviolett(UV)-Licht-induzierte Melanogenese. Pathophysiologisch sind sie über den MC1R-Signalweg auch für die kutane Hyperpigmentierung beim Morbus Addison, ektopen POMC(Proopiomelanokortin)-Syndrom oder bei anderen Zuständen mit erhöhten Melanokortinblutspiegeln verantwortlich. Translationale Forschung an α‑MSH (Melanozyten-stimulierendes Hormon) und dessen Antagonisten hat neben der Melaninpigmentierung zahlreiche andere biologische Wirkungen deutlich gemacht, die von Zytoprotektion, antioxidativen Effekten, Immunmodulierung, Regulierung von Kollagenmetabolismus und Fibrose, Talgproduktion bis zur Wundheilung reichen. Für die Entwicklung neuartiger Therapien innerhalb der klinischen Dermatologie waren diese Ergebnisse auch für die klinische Erprobung synthetischer α‑MSH-Analoga wie Afamelanotid wegweisend. Dieses Melanokortinpeptid wurde 2015 als erstes synthetisches α‑MSH-Analogon zur Behandlung der erythropoetischen Protoporphyrie zugelassen. Neben Afamelanotid besitzt Setmelanotid als synthetischer MC4R-Agonist vielversprechende klinische Wirkungen bei bestimmten Formen der genetisch bedingten Adipositas wie der POMC-Defizienz. Zukunftsperspektiven ergeben sich in der Dermatologie in der breiteren Anwendung von α‑MSH-Analoga, entweder topisch oder systemisch, bei anderen noch unzureichend behandelbaren Dermatosen, zudem in der klinischen Erprobung von Melanokortinpeptidderivaten, die nicht das zentrale melanotrop wirkende Pharmakophor aufweisen, aber trotzdem antientzündlich wirken.
Abstract
Melanocortins are peptides that share a common central pharmacophor. Melanin pigmentation of interfollicular epidermis and hair via MC1R remains the key physiologic function of the naturally occurring melanocortin peptides in skin. Moreover, the melanocortins are crucially involved in the ultraviolet light-induced tanning response. Under pathophysiologic conditions, melanocortin peptides induce cutaneous hyperpigmentation, likewise via the MC1R axis, e.g. in patients with Addison’s disease, ectopic precursor pro-opiomelanocortin (POMC) syndrome and in those with abnormally elevated melanocortin blood levels. Translational research on α‑MSH (melanocyte-stimulating hormones) and their antagonists has further revealed a variety of other biological activities beyond pigmentation. They include cytoprotection, antioxidative effects, regulation of collagen metabolism and fibrosis, sebum production, and cutaneous wound healing. These findings have also promoted the development of novel therapies in clinical dermatology including the exploitation of afamelanotide. In 2015, this agent became the first in-class synthetic α‑MSH analogue to be approved in dermatology for the treatment of erythropoetic protoporphyria. In addition to afamelanotide, setmelanotide has recently emerged as a highly selective MC4R agonist useful for the treatment of distinct forms of genetically determined obesity, e.g., POMC deficiency. Future perspectives in dermatology reside in treatment of other difficult-to-treat skin diseases with α‑MSH analogues, either with topical or systemic formulations. Moreover, synthetic melanocortin peptide derivatives lacking the central pharmacophor but with maintained anti-inflammatory effects could become a promising strategy for the design of new therapies in dermatology.
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M. Böhm gibt an, dass er Studienleiter einer von der Firma Clinuvel gesponserten Phase-II-Studie von Afamelanotid bei Patienten mit Akne war, beratend für die Firma tätig war und finanzielle Unterstützung von der Firma für die Durchführung von Symposien über Melanokortine erhalten hat. M. Böhm gibt auch an, dass er finanzielle Unterstützung von der Firma Wolff Bielefeld für In-vitro-Versuche zu KdPT an Keratinozyten erhalten hat. Dieser Beitrag enthält keine Studien am Menschen.
Für diesen Beitrag wurden vom Autor keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.
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Böhm, M. Melanokortinpeptide. Hautarzt 71, 741–751 (2020). https://doi.org/10.1007/s00105-020-04680-6
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DOI: https://doi.org/10.1007/s00105-020-04680-6
Schlüsselwörter
- Melanokortinrezeptoren
- Melanozyten-stimulierendes Hormon
- Afamelanotid
- Setmelanotid
- Melanokortinpeptidderivate