Vitiligo is a depigmentation disease, the main pathological feature is the loss of skin melanocytes function, unable to secrete melanin normally, resulting in white patches on the surface of the skin. In layman’s terms, it is the melanocyte cells in vitiligo patients who are damaged.
Peptide drug synthesis technology has become increasingly mature, but enzymes in the human body are easy to degrade peptides, and the short residence time of peptides in the body is the key to limiting the research and development of peptide drugs. Shi Junfeng’s research group at the Interdisciplinary Institute of Life Medicine of Hunan University discovered a “Lego” self-assembling peptide molecule, and the jelly-like gel formed can greatly improve its residence time in the human body. This peptide activates the melanin production pathway and effectively treats vitiligo.
Recently, this result was published in ACS Nano, with Zhu Ci, a master’s student and Li Tingting, a doctoral student, from the Interdisciplinary Institute of Life and Medicine of Hunan University, as the first author, and Shi Junfeng as the corresponding author.
Shi Junfeng (far left) and team members conduct relevant experiments. Photo courtesy of interviewee
Find the “way” to regulate melanocytes
From the vitiligo hospitals that are common in large and small cities, it can be seen that this is a more common disease, with a global incidence of 0.5% to 2.0%. According to statistics, there are currently about 30 million vitiligo patients in China, of which young adults are the primary population.
“Most of the vitiligo hospitals that advertise all kinds of secret recipes and remedies lack effective drugs.” Shi Junfeng said that at present, the US Food and Drug Administration and the European Medicines Agency have not approved any specific drugs for the treatment of vitiligo. Clinically, the treatment of vitiligo can be divided into light therapy, surgical treatment and local treatment, but its side effects are large and easy to recur. Therefore, it is crucial to develop new drugs to treat vitiligo.
Melanocorticin receptor (MCR) is a G protein-coupled receptor with 5 isotypes (MC1R-MC5R) that regulate different physiological functions. Among them, MC1R is closely related to skin and hair pigmentation, so MC1R is a potential target for vitiligo treatment.
MC1R binds to melanocytes stimulating MSH to stimulate melanocytes to synthesize melanin through a series of cascade reactions. However, there are three subtypes of MSH, and a single subtype can regulate several MCR members at the same time, which is not specific. Therefore, the development of a drug that specifically regulates MC1R is critical.
“MSH can not only regulate pigment production, but also regulate appetite, sexual desire, immunity and other physiological activities, and its regulatory mechanism is complex and not ‘specific’ enough.” What we need to do is to find an exclusive pathway to regulate MC1R, so that the drug can accurately ‘lead the way’ to treat vitiligo. Shi Junfeng said.
In the preliminary work, the cooperative research team found that γ-MSH analogues have good selectivity and efficiency in MC1R. Unfortunately, the linear polypeptide is easy to degrade, has a short half-life, and generally has no efficacy in less than 30 minutes, making it difficult to become a drug.
Discover self-assembling “LEGO” peptides
Peptides are intermediate products of protein hydrolysis. Enzymes in the human body can degrade peptides, and their poor stability is a key problem that limits the drug use of peptides. By the end of 2020, there were about 80 peptide drugs in the global market, a large proportion of which targeted the G protein-coupled receptor family.
“The G protein-coupled receptor family has a high potential for drug domination, and we have been focusing on it in a targeted manner.” Shi Junfeng said that on the basis of a large number of experiments, the research group stumbled upon a peptide MC1R agonist, which can automatically assemble and form a gel under physiological conditions. Agonists are relative to inhibitors, which are a class of molecules that enhance activity.
The function of peptide MC1R agonists is to activate MC1R and make it synthesize more melanin. “These agonists are able to spontaneously drive assembly to form new polymers with specific structures (big houses) like self-assembled Lego (bricks).” Shi Junfeng said that the body’s enzymes can degrade individual peptide molecules, but when the peptide is automatically assembled, it is like changing from a chopstick to a bundle of chopsticks, and the enzyme will “fold” a bundle of chopsticks.
After verifying the function of the drug at the cellular level, team members Zhu Ci and Wang Zhuole rushed to the slaughterhouse in the middle of the night to obtain freshly slaughtered pig skins for experiments. It was found that the agonist specifically bound to MC1R promoted melanin production by upregulating tyrosinase activity, tyrosine-associated protein, and tyrosinase protein expression levels. It can effectively promote melanin production in pig skin and mice, and the gel preparation has better efficacy than free polypeptide molecules.
Team members prepare to measure the effects of drugs for shaving lab animals. Photo courtesy of interviewee
“The previous peptide drug was degraded in less than half an hour, and the newly developed gel formulation still has 50% remained in bovine serum protein for 48 hours.” Shi Junfeng said.
At present, the gel formulation is undergoing transdermal drug delivery research, and has filed for PCT patents and Chinese patents, and has also obtained funding from biopharmaceutical companies and is conducting clinical translational research. “Patients often do not have a high acceptance of injected drugs, so we made it into a microneedle to reduce the pain caused by injection, and we hope to further make it into a cosmetic application in the later stage, and apply it to treat vitiligo.” Shi Junfeng said.
According to reports, the achievement is the first systematic study of the treatment of vitiligo by regulating the function of MC1R, and provides a candidate for new drugs for the treatment of vitiligo.
According to the reviewers, the study found an MC1R agonist that self-assembles to form fiber-rich hydrogels under physiological conditions. Moreover, the agonist can promote skin pigmentation by upregulating the expression of tyrosinase and tyrosine-related proteins, so it is expected to become a new drug for the treatment of vitiligo. This research is very meaningful and has extremely high translational value in translational medicine.
The research was supported by the National Youth Top Talent Support Program, the National Natural Science Foundation of China, the Natural Science Foundation of Hunan Province, and the Hunan University Start-up Fund. (Source: Wang Haohao, China Science News)
Related paper information:https://pubs.acs.org/doi/10.1021/acsnano.3c01960