A-MSH: An Emerging Anti-Inflammatory Antimicrobial Peptide
Alpha-Melanocyte Stimulating Hormone: An Emerging Anti-Inflammatory Antimicrobial Peptide
2014
Abstract
The alpha-melanocyte stimulating hormone (?-MSH) is a neuropeptide belonging to the melanocortin family. It is well known for its anti-inflammatory and antipyretic effects and shares several characteristics with antimicrobial peptides (AMPs). There have been some recent reports about the direct antimicrobial activity of ?-MSH against various microbes belonging to both fungal and bacterial pathogens. Similar to ?-MSH's anti-inflammatory properties, its C-terminal residues also exhibit antimicrobial activity parallel to that of the entire peptide. This review is focused on the current findings regarding the direct antimicrobial potential and immunomodulatory mechanism of ?-MSH and its C-terminal fragments, with particular emphasis on the prospects of ?-MSH based peptides as a strong anti-infective agent.
Introduction
?-MSH is an endogenous neuropeptide derived from proopiomelanocortin (POMC), a common precursor protein of all melanocortin peptides, which expresses in the pituitary gland. It is primarily a pigmentary hormone of the vertebrates and largely influences immune reactions in the host for controlling inflammation in the brain and peripheral organs. Both in vitro and in vivo studies have confirmed that, inside the host, ?-MSH reduces the concentration of proinflammatory mediators through the induction of cyclic adenosine monophosphate (cAMP) and inhibition of the nuclear factor ?? (NF-??), thus protecting the brain and peripheral organs from inflammatory disorders.
The presence of the ancestral components of host immunity—AMPs—has been reported across all classes including human, and their immunomodulatory role has been widely implicated in fighting against infection. Similar to AMPs, ?-MSH is a short peptide, cationic in nature. Although the primary site of ?-MSH expression is pituitary gland, its presence in defense cells and several peripheral sites including skin pointed towards its immunoregulatory properties. These characteristics of ?-MSH openly suggest its role in host immunity, specifically innate immunity, and provide a platform to look for its direct antimicrobial properties. Over the last decade, a number of independently conducted studies have demonstrated the antimicrobial activity of ?-MSH as well as its C-terminals (containing Lys-Pro-Val) against a wide range of microbes including Candida albicans, Escherichia coli, and Staphylococcus aureus.
A major hurdle faced in developing drugs based on natural AMPs is the occurrence of inflammation. Due to this, the development of new anti-infective agents with both antimicrobial and anti-inflammatory properties has got serious attention in recent years. This is where ?-MSH comes across as unique compared to other natural AMPs—it is endogenous anti-inflammatory, antipyretic neuropeptide combined with antimicrobial properties. We present here the in-depth analysis of the current evidences supporting the direct antimicrobial and immunomodulatory potential of ?-MSH and analogues. This paper is aimed at emphasizing the future perspectives of ?-MSH as a therapeutic against microbial infection in humans.
Biochemistry of Melanocortin Peptides
Melanocortin (MC) peptides are derived from proopiomelanocortin (POMC) and include adrenocorticotropic hormone (ACTH); ?-lipoprotein hormone (?-LPH); ?-, ?-, and ?-MSH; and corticotrophin-like intermediate peptide (CLIP). In higher vertebrates, the POMC gene is expressed predominantly in the pituitary (intermediate lobe) gland, but its expression has been detected widely in peripheral tissues as well. Melanocortin is an ancient peptide family that has existed since the Paleozoic Era, and the expression of POMC has been recognized in lamprey, an earliest vertebrate.
All melanocortins work through interaction with melanocortin receptors (MCRs); thus MC peptides have in common a four amino acid long core sequence—His-Phe-Arg-Trp (HFRW)—which works as both the message sequence and the address sequence and activates the MCRs. MCRs belong to the rhodopsin family of G protein coupled receptors (GPCRs). There are five MCRs]
Alpha-Melanocyte Stimulating Hormone (?-MSH)
?-MSH is generated as a result of post-translational processing of POMC by serine proteinases called prohormone convertases 1 and 2 (PC1 and PC2). PC1 cleaves POMC at arginine or lysine residue and produces ACTH, ?-MSH, and ?-LPH. Thereafter, a second proteinase PC2 cleaves ACTH to give CLIP and ?-MSH. ?-MSH is produced from the cleavage of ?-LPH. ?-MSH is a 13 amino acid (AC-S1Y2S3M4E5H6F7R8W9G10K11P12V13-COOH) long, cationic peptide. The N-terminal of ?-MSH is acetylated and C-terminal is amidated after posttranslational modification. ?-MSH is widely secreted from pituitary gland of central nervous system (CNS) to several peripheral cells.
Thus, ?-MSH performs two types of biological functions based on its (i) hormonal effects such as melanin synthesis, secretion of sebum, regulation of temperature, control of pain, and regulation of behavior involving sex, feeding, and learning and (ii) immunomodulatory effects such as the cure of several inflammatory conditions of brain (meningitis, vasculitis, etc.) and peripheral organs (arthritis, colitis, etc.) and immunosuppression. In addition to this, various studies have supported the protective influence of ?-MSH in mouse models of neurodegenerative diseases such as Alzheimer's by improving the memory.
Until two decades ago this neuropeptide was primarily known as melanogenic hormone; however, later its immunomodulatory role was discovered and its anti-inflammatory effects were implicated in the cure of many inflammatory conditions.
Conclusions
In this postantibiotic era, AMPs have already created huge hopes for their host defense mechanism and several of these peptides find ways into medical practice although the numbers are less than expected. The development of AMPs as therapeutic alternatives to combat the resistant pathogenic microbes is facing problems, majorly due to the enhanced inflammatory reactions associated with them and their potential for toxicity. ?-MSH overcomes both of these issues being anti-inflammatory and nontoxic. This endogenous neuropeptide was initially characterized as a pigment producing peptide and later received serious attention due to its potent protective and anti-inflammatory activity. ?-MSH performs these actions by binding to centrally expressed melanocortin receptors, which subsequently coordinate numerous anti-inflammatory pathways leading to shutting down all the downstream effector proinflammatory mechanisms. Besides anti-inflammation, it also exhibited immunosuppression in case of skin-inflammatory diseases like psoriasis. The striking resemblance of this anti-inflammatory neuropeptide with cationic AMPs compelled the scientists to further explore its antimicrobial efficacy. Indeed, ?-MSH appeared to possess potent antimicrobial activity against pathogens from different classes like C. albicans, S. aureus, E. coli, and more. It also adopts variable approaches to kill different microbes. For instance, it kills fungal cells through the induction of cAMP and bacterial cells by damaging the membrane. The C-terminal region (KPV) of ?-MSH demands special attention for several reasons. It exhibits in vitro and in vivo anti-inflammatory activity similar to that of parent peptide without melanotropic effect. This observation removes the main obstacle in developing ?-MSH based peptides as therapeutics, which is nothing, but its pigmentary effects and KPV are devoid of that. Moreover, this essential anti-inflammatory sequence, that is, C-terminal tripeptide (KPV) of ?-MSH, is also essential for its direct antimicrobial efficacy. Therefore, this short molecule KPV appears to have tremendous potential to be developed as therapeutic agent as it is more suitable for clinical use and demands further research. The dimer of this short peptide, that is, (CKPV)2 being both anti-inflammatory and antimicrobial, is already in clinical trial and will definitely make its way to enter into medical practice in near future.
The pleiotropic effects of ?-MSH and its C-terminal peptides, including their anti-inflammatory, immunosuppressive, antipyretic, and antimicrobial activities, are unique. These endogenous properties make them the most promising antimicrobial host defense peptides. More work is however needed to bring these peptides from the lab to clinic. First, a deeper corelation is required to be established between its anti-inflammatory and anti-infective reactions through the in vivo models of infections. Second, further biophysical studies are required to design a potent ?-MSH based AMP with enhanced killing and immunomodulatory activities. Third, the possibility of resistance developing against this peptide needs to be ruled out. Fourth, overall safety profile of these peptides particularly with ?-MSH fragments requires to be vigorously examined.
In conclusion, ?-MSH, its analogues, and related C-terminal tripeptide with broad-spectrum antimicrobial activity combined with immunomodulating effects and no cytotoxicity could emerge as excellent therapeutic agents against resistant pathogens.
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