Up- or Downregulation of Melanin Synthesis Using Amino Acids, Peptides, and Their Analogs

Abstract

Harmonious synthesis and distribution of melanin in the skin contribute to the expression of beauty and the maintenance of health. When skin pigmentary disorders occur because of internal or external factors or, when there is a need to artificially increase or reduce the pigmentation level of the skin for aesthetic or therapeutic purposes, various pharmacological therapies are applied but the results are not always satisfactory. Studies have been conducted to improve the efficacy and safety of these treatment strategies. In this review, we present the latest studies regarding peptides and related compounds that may be useful in artificially increasing or reducing skin melanin levels. Certain analogs of α-melanocyte stimulating hormone (MSH) and oligopeptides with the sequences derived from the hormone were shown to promote melanin synthesis in cells and in vivo models. Various amino acids, peptides, their analogs, and their hybrid compounds with other chemical moieties were shown to inhibit tyrosinase (TYR) catalytic activity or downregulate TYR gene expression. Certain peptides were shown to inhibit melanosome biogenesis or induce autophagy, leading to decreased pigmentation. In vivo and clinical evidence are available for some compounds, including [Nle⁴-_D-Phe⁷]-α-MSH, glutathione disulfide, and glycinamide hydrochloride. For many other compounds, additional studies are required to verify their efficacy and safety in vivo and in clinical trials. The accumulating information regarding pro- and antimelanogenic activity of peptides and related compounds will lead to the development of novel drugs for the treatment of skin pigmentary disorders.

Keywords: agonist; amino acid; antagonist; autophagy; inhibitor; melanin; melanocortin 1 receptor; melanogenesis; melanosome biogenesis; peptide; pigmentation; tyrosinase.

Figure 1

The major targets of amino acids, peptides, and their analogs for the control of skin pigmentation. Microphthalmia-associated transcription factor (MITF) plays a primary role in inducing gene expression of melanogenic enzymes, such as tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT) in response to various internal and external stimuli. In addition to the α-melanocyte stimulating hormone (MSH)/ melanocortin 1 receptor (MC1R) /adenyl cyclase (AC)/ cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element-binding protein (CREB) pathway, the stem cell factor (SCF)/receptor tyrosine kinase protein, c-Kit/mitogen-activated protein kinases (MAPK) pathway, and WNT/frizzled/glycogen synthase kinase (GSK) 3β/β-catenin pathway can activate MITF. Other signaling pathways, such as phospholipase C (PLC)/diacylglycerol (DAG)/protein kinase C (PKC) β cascade, and nitric oxide (NO)/cGMP/protein kinase G (PKG) cascade are also involved in the activation of MITF. Melanosome biogenesis occurs through morphologically distinct stages 1, −2, −3, and −4. Melanogenic enzymes matured through post-translational modifications in endoplasmic reticulum and metal-loading in Golgi apparatus are sorted and transported to stage 2 melanosomes. Melanin is synthesized thereafter and the mature stage 4 melanosomes with accumulated melanin are transferred through dendrites to keratinocytes.

Figure 2

Sequences of proopiomelanocortin (POMC)-derived peptide hormones and synthetic peptides with melanogenic or antimelanogenic effects. (a) The entire amino acid sequence of the human POMC protein is shown. Sequences for different POMC-derived hormones are indicated with different colors: adrenocorticotrophic hormone (ACTH) in blue; α-melanocyte stimulating hormone (MSH) in underlined blue; β-MSH in green; γ₃-MSH in red; and γ₁-MSH in underlined red. (b) Amino acid sequences of ACTH, α-MSH, β-MSH, γ₃-MSH, and γ₁-MSH including posttranslational modifications are shown. A conserved sequence, His-Phe-Arg-Trp, is highlighted. (c) Tetrapeptides that stimulate melanin synthesis [62]. (d) A pentapeptide that stimulates melanin synthesis [63]. (e) Tetra-, tri-, di-, and mono-peptides that inhibit melanin synthesis [125]. (f) Molecules with no or unclear effects on melanin synthesis [61,125].