Peptides and Proteins

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Chapter 17 Peptides and Proteins

TERMINOLOGY AND DEFINITIONS

Peptides are short chains of amino acid sequences that make up larger proteins. There are three main categories of peptides currently being used in cosmeceutical products (Box 17.1). This increase in peptide technology has arisen because of the technology to synthesize fragments that mimic peptide sequences in collagen and elastin with the ability to stimulate production of new collagen and elastin. Other peptides are currently available that function primarily as carriers of cofactors for important enzymatic steps in collagen production. Peptide fragments also exist that are able to modulate neurotransmitter release. Since some wrinkling of the skin is caused by collagen breakdown, while other wrinkles are caused by hyperkinetic facial muscle movement, peptides that have actions to inhibit or reverse these actions could have clinical antiaging cosmeceutical benefits.

INDICATIONS AND BIOLOGIC ACTIVITY

Clinically, photoaged skin has wrinkles that are coarse, while the wrinkles of naturally aged skin are much finer. Both of these wrinkles are due, in part, to the loss of collagen in the skin. Chronologically aged skin shows decreased production of new collagen, as well as increased proteolytic activity resulting in increased collagen degradation. Aging fibroblasts show decreased synthesis of mRNA for type I collagen, which is the major collagen in the skin. Also, in skin cell cultures, aging fibroblasts proliferate at a slower rate than fetal fibroblasts. Therefore, natural aging is at least partly the result of the limited replicative capacity of dermal fibroblasts, as well as the overexpression of proteolytic activity of matrix metalloproteinase-1 (MMP-1, interstitial collagenase).

Additionally, both photoaged and naturally aged human skin have lower procollagen type I mRNA and protein compared to younger skin. The balance between collagen synthesis and collagen breakdown appears to be different in the same individual from photoaged to naturally aged skin. While both show greater MMP activity, it is even higher in the skin aged from ultraviolet (UV) radiation exposure. The precocious elastosis seen in actinically damaged skin is also at least partially responsible for the difference in the appearance of the sun-induced versus age-induced wrinkling. The elastotic degeneration of sun-damaged skin may be due to chronic injury to fibroblasts that results in thicker elastotic fibers with accentuated microfibril dense masses. In the photoaged skin, both mRNA and protein production are reduced when compared to sun-protected skin of the same individual. UV radiation is well known to stimulate MMP-1, which in turn damages and degrades collagen. It is likely that the degraded and damaged collagen has further deleterious effects on dermal fibroblast function after repeated injury. Thus, there is a need for cosmeceuticals capable of either increasing collagen regeneration or preventing its further demise. Peptides and proteins for antiaging purposes were developed with this end in mind.

• Signal peptides

It is well recognized that the ability to stimulate proteins of the extracellular matrix, including collagen and elastin, or to diminish the activity of collagenase, or both, could result in clinical improvement of the wrinkles and lines that are seen in both photoaged and naturally aged skin. Thus, direct stimulation of collagen-producing human fibroblasts and/or downregulation of fibroblast collagenase production are the mechanisms by which a cosmeceutical may clinically improve lines and wrinkles. Bioactive peptides were originally developed as part of wound-healing research on the growth and stimulation of human skin fibroblasts. These same peptides are now being studied for their ability to act as growth factors via activation of protein kinase C, a key enzyme for cell growth and migration. Wound studies of human keratinocyte cultures show a stimulatory effect from topical application of neuropeptides, such as gastrin-releasing peptide. Certain amino acid chains in specific lengths and sequences have been found to stimulate human skin dermal fibroblast growth in vitro. One study of elastin-derived peptides showed that valine-glycine-valine-alanine-proline-glycine (VGVAPG) significantly stimulated human skin fibroblast production, probably mediated through a binding of the peptide to a plasmalemmal receptor of human skin fibroblasts. This same hexapeptide sequence has been found to stimulate human dermal skin fibroblasts, downregulate elastin expression, and to be chemotactic for fibroblasts. Other studies have shown the peptide sequence tyrosine-tyrosine-arginine-alanine-aspartame-aspartame-alanine (YYRADDA) to inhibit procollagen C-proteinase, which cleaves C propeptide from type I procollagen. This could result in decreased collagen breakdown. A specific amino acid sequence, lysine-threonine-threonine-lysine-serine (KTTKS), found on type I procollagen, has been found to stimulate feedback regulation of new collagen synthesis, resulting in an increased production of extracellular matrix proteins. A number of these signal peptides have made the transition from research to practical application.

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