Certain analogs of α-melanocyte stimulating hormone (MSH) and peptides with the sequences derived from the hormone were shown to promote or suppress 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 [Nle 4-D-Phe 7]-α-MSH, glutathione disulfide, and glycinamide hydrochloride.
Melanin plays an important role in the appearance of skin color, protection against ultraviolet (UV) radiation, and maintenance of homeostasis in many organs. Both over- and underproduction of melanin are a major research theme in cosmetology and dermatology, not only from the aesthetic viewpoint pursuing a harmonious skin tone, but also from a medical viewpoint preventing and treating various skin diseases.
As numerous amino acids and peptides directly and indirectly participate in the melanin synthesis process, it is reasonably assumed that the process could be artificially regulated by certain structurally related compounds. This review will introduce recent advances in the artificial regulation of skin pigmentation using amino acids, peptides, and their analogs.
The most-studied molecular targets are the receptors on the surface of melanocytes which transmit intracellular signals, and the enzymes and proteins within melanocytes involved in melanin synthesis, and melanosome biogenesis and autophagy in melanocytes (Figure 1).
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.
In this chapter, we discuss promotion of melanin synthesis by α-MSH analogs and oligopeptides derived from the hormone sequence, L-Tyr and L-DOPA, and other peptide hormones. Selected studies are listed in Table 1.
In this chapter, we discuss basic amino acids and peptides (Section 4.1), peptides isolated from plants or derived from natural protein sequences (Section 4.2), and hybrid peptides with other chemical moieties (Section 4.3) that inhibit TYR catalytic activity in vitro. We additionally discuss certain peptides that downregulate TYR gene expression or its protein level in melanocytes (Section 4.4). Finally, we discuss the peptides that inhibit melanosome biogenesis or induce autophagy in melanocytes (Section 4.5). IC 50 is defined as the 50% inhibitory concentration.
Various amino acids and peptides are known to inhibit TYR activity and/or cellular melanin synthesis, and some of them show depigmenting effects in human skin (Table 2).
Various peptides derived from natural protein sequences inhibit TYR activity and display antimelanogenic effects in cells (Table 3).
Some amino acids and peptides have been hybridized with other antimelanogenic compounds, such as kojic acid, protocatechuic acid, α-resocylic acid, gentisic acid, gallic acid, caffeic acid, para-coumaric acid, and ascorbic acid to improve their activity, stability, or bioavailability (Table 4).
