Peptidomimetics for Cosmetic Applications

Sep 1, 2013 | Contact Author | By: Steven Isaacman, PhD, Nanometics LLC; Michael Isaacman, University of California Santa Barbara; and Sung Bin Y. Shin, PhD, Avon Products
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Title: Peptidomimetics for Cosmetic Applications
peptidomimeticsx peptidex antibioticx penetrationx antimicrobialx peptoidsx
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Keywords: peptidomimetics | peptide | antibiotic | penetration | antimicrobial | peptoids

Abstract: Peptidomimetics, or synthetic bioactive peptides, have been developed that mimic the biological functions of peptides and proteins but overcome many of these challenges and limitations. Further, due to their wide range of activity, synthetic feasibility and ease of handling, they have played a vital part in biological research. This column will discuss the potential application of these short chain oligomers in cosmetics and personal care.

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S Isaacman, M Isaacman, SBY Shin, Peptidomimetics for Cosmetic Applications, Cosm & Toil 128(9) 612 (2013)

Bioactive peptides are capable of inducing biological responses by stimulating cell surface receptors, inhibiting protein-protein interactions, inducing protein conformational rearrangements, inactivating enzymes, regulating gene expression levels, etc. However, their inherent proteolytic instability, poor transport properties into the bloodstream and across the blood-brain barrier, rapid excretion through the liver and/or kidneys, and reduced efficacy due to inherent structural flexibility make them poor candidates for systemic drug delivery molecules.1

In turn, peptidomimetics, or synthetic bioactive peptides, have been developed that mimic the biological functions of peptides and proteins but overcome many of these challenges and limitations. Further, due to their wide range of activity, synthetic feasibility and ease of handling, they have played a vital part in biological research. This column will discuss the potential application of these short chain oligomers in cosmetics and personal care.

Peptide vs. Peptidomimetic

While the use of bioactive peptides in oral drug delivery applications is still a great challenge, skin-targeted topical applications present unique opportunities. Proteolytic degradation and rapid excretion are less of an issue for the cosmetic application of bioactive peptides. In fact, in the past decade, chemically modified bioactive peptides have been introduced for topical cosmetic applications. Examples include topical palmitoyl pentapeptide, which stimulates collagen production;2 copper tripeptide-1, which promotes wound healing;3 and one synthetic hexapeptide that mimics the action of botulinum neurotoxins (BoNTs).4

The palmitoyl pentapeptide incorporates a hydrophobic palmitoyl group to enhance cellular penetration and also to resist degradation by N-terminal exopeptidases. Copper tripeptide-1 leverages copper complexation, which confers N-terminal exopeptidase resistance and reduces the number of available hydrogen bonding sites, thereby enhancing cellular permeation parameters. The hexapeptide incorporates an acetyl group on the N-terminus and amidation on the C-terminus of the hexapeptide, which enhances the resistance toward both N-terminal and C-terminal exopeptidases. Although the modifications to these cosmetic bioactive peptides represent steps forward, still, these peptides are susceptible to degradation by endopeptidases, they exhibit less than optimal cross membrane transport properties, and they provide limited efficacy due to structural heterogeneity. Peptidomimetics, on the other hand, are designed to address these challenges. Some examples include azapeptide, beta-peptide, peptoid, vinylogous sulfonopeptide, oligocarbamate and oligourea (see Figure 1). These oligomers utilize non-natural oligomer backbones, making them resistant to both exopeptidases and endopeptidases.5 Moreover, beta-peptides, peptoids and vilylogous sulfonopeptides have been shown to provide enhanced cell permeation mainly due to increased hydrophobicity and reduced hydrogen-bonding capacity.6 Peptidomimetics also increase structural homogeneity by stiffening the main chain, and unlike peptides, they can readily incorporate conformation constraining motifs and implement head-to-tail macrocyclization. Such modifications have been demonstrated to increase the structural homogeneity and enhance biological activity.7

Further, the cellular responses stimulated by both bioactive peptides and peptidomimetic oligomers depend heavily on the highly specific three-dimensional structures they generate. Peptidomimetic oligomers exhibit vital functional groups found in the proteins whose functions they replicate in a precise geometry. Such spatial arrangements are used as the recognition motif by the biological macromolecules, and are essential in inducing biological function.8 This three-dimensional structural requirement is a challenging task to fulfill, especially for shorter chain length peptides. Largely due to the limited number of available canonical amino acid building blocks, the variety of sequences and structures peptides can generate is limited. However, a much wider range of non-natural building blocks or side chains is readily available for peptidomimetics, thus providing greater chemical and structural diversity.

The continued development of peptidomimetics research and the accumulation of bioactive peptidomimetic oligomers have generated a large volume of information on the therapeutic potential of these molecules. In fact, a number of peptidomimetic therapeutic agents are currently being studied under various stages of clinical trials, and several have already been approved by the U.S. Food and Drug Administration (FDA). The molecules in consideration are not restricted to a particular family of molecules, but rather represent a wide variety of classes of molecules such as protease inhibitors,9 dopamine receptor modulators,10 antivirals and antimicrobial agents.11 The clinical trial data, so far, is promising.

In one case, a peptidomimetic allosteric modulator PAOPA has been shown to be clinically safer than current typical antipsychotic drugs.10 Furthermore, peptidomimetic antimicrobial agents are gaining a greater acceptance over antimicrobial peptides (AMPs). Even though there are thousands of naturally occurring AMPs, only few of them have been approved by the FDA, and their uses are limited to topical applications only. AMPs are discouraged from systemic use because a large number of AMPs trigger host immune response. Recent clinical studies involving peptidomimetic antimicrobial agents reveal that peptidomimetics are proving to be both efficacious and safe.11

Peptidomimetics as Topical Antibiotics

The recent insurgence of multi drug-resistant (MDR) bacterial strains has prompted the field of peptidomimetic research to develop synthetic antimicrobial agents. In relation, peptoids—N-substituted polyglycine oligomers, in particular—have seen a great deal of development. For one, the Barron Group at Stanford University has been successful in developing synthetic mimics of naturally occurring antimicrobial peptides (AMPs). These oligomers utilize facially segregated hydrophobic and cationic surfaces to impart antimicrobial activity.12 Similar studies conducted by the Kirshenbaum Lab at New York University has provided high resolution electron microscope images confirming the mechanism of action of these antimicrobial peptoids.13

Antimicrobial peptoids selectively target the cellular membrane of methicillin-resistant Staphylococcus aureus (MRSA), damaging the membrane by forming pores. Since these antimicrobial agents target cellular membranes, the development of bacterial resistance against these agents is expected to be reduced. Furthermore, safety studies of these oligomers have demonstrated they are inert toward human cells. The highly selective nature of peptoid antimicrobial agents, in conjunction with their proteolytic resistance and reduced propensity for bacterial resistance, make them ideal candidates as therapeutic agents against MDR bacterial strains. Topical applications of these agents are currently being evaluated.

Peptidomimetics and Cellular Penetration

Cellular penetration represents the greatest hurdle in the development of bioactive oligomers. Much effort has been made toward understanding the parameters that facilitate transport across the cellular membrane. In one study, the Kodadek Lab at the University of Texas Southwestern Medical Center has compared the permeability ratio of peptides to their analogous peptoids. The study showed that peptoid analogs were more than 20 times more permeable than the peptide counterparts.6 In a follow-up study, Kodadek generated a randomized library of 350 steroid-peptide conjugates, along with 350 steroid-peptoid conjugates. This study revealed that peptoids were 3 to 30 times more permeable than peptides (p < 0.01).14 Kodadek attributes this difference in permeability to the solubility, polar surface area, and hydrogen-bonding capacity, which are considered to be three of the most widely accepted parameters affecting cell membrane permeability.

Peptoids impart lower lipophilicity, compared with their peptide counterparts. This makes peptoids more soluble in physiological conditions. Computational calculations revealed that peptoids exhibit an overall lower polar surface area. Lastly, peptides and the peptoid analogs have the same number of hydrogen bond acceptors, but peptides have more hydrogen bond donors. This is mostly due to the fact that peptides have amide hydrogens, which are capable of forming hydrogen bonds, whereas peptoids have tertiary amides lacking hydrogens. Peptoids have inherent propensity for higher cellular permeation potential. This family of oligomers represents an attractive platform to which bioactive oligomers can be developed.


Overall, peptidomimetics have the potential to greatly impact the skin care market due to their enhanced efficacy. This primarily is due to their increased stability, which leads to favorable dose-to-duration ratios; increased delivery; and increased versatility, based on an enhanced solubility profile.

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2. LR Robinson et al, Topical palmitoyl pentapeptide provides improvement in photo-aged human facial skin, Int J Cosm Sci 27(3) 155–160 (2005)
3. F Gorouhi and H I Maibach, Role of topical peptides in preventing and treating aged skin, Int J Cosm Sci 31(5) 327–345 (2009)
4. C Blanes-Mira et al, A synthetic hexapeptide with antiwrinkle activity, Int J Cosm Sci 24(5) 303–310 (2002)
5. JA Patch and AE Barron, Mimicry of bioactive peptides via non-natural, sequence-specific peptidomimetic oligomers, Curr Opin Chem Bio 6(6) 872–877 (2002)
6. YU Kwon and T Kodadek, Quantitative evaluation of the relative cell permeability of peptoids and peptides, J Am Chem Soc 129(6) 1508–1509 (2007)
7. SBY Shin et al, Cyclic peptoids, J Am Chem Soc 129(11) 3218-3225 (2007)
8. AD Bautista et al, Sophistication of foldamers form and function in vitro and in vivo, Curr Opin Chem Bio, 11(6) 685–692 (2007)
9. G Fear et al, Protease inhibitors and their peptidomimetic derivatives as potential drugs, Pharmacol Ther, 113(2) 354–368 (2007)
10. ML Tan et al, Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic, PAOPA: examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia, Peptides (42) 89–96 (2013)
11. MA Scorciapino and AC Rinaldi, Antimicrobial peptidomimetics: reinterpreting nature to deliver innovative therapeutics, Front Immunol 3(171) 1–4 (2012)
12. NP Chongsiriwatana et al, Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides, Proc Natl Acad Sci USA 105(8) 2794–2799 (2008)
13. ML Huang et al, Amphiphilic cyclic peptoids that exhibit antimicrobial activity by disrupting Staphylococcus aureus membranes, Eur J Org Chem (17) 3560–3566 (2013)
14. NC Tan et al, High-throughput evaluation of relative cell permeability between peptoids and peptides, Bioorg Med Chem 16(11) 5835–5861 (2008)



Figure 1. Example peptidomimetic structure schematics

Figure 1. Example peptidomimetic structure schematics

Some examples include azapeptide, beta-peptide, peptoid, vinylogous sulfonopeptide, oligocarbamate and oligourea (see Figure 1).

Footnotes (CT1309 Isaacman)

a Matrixyl (INCI: Glycerin (and) Butylene Glycol (and) Water (aqua) (and) Carbomer (and) Polysorbate-20 (and) Palmitoyl Oligopeptide (and) Palmitoyl Tetrapeptide-3) is a product of Sederma,
Argireline (INCI: Acetyl Hexapeptide-3) is a product of Lipotec,

Biography: Steven Isaacman, PhD, Nanometics LLC

Steven Isaacman, PhD, earned a master’s degree in organic chemistry from Stony Brook University, and a Master of Science and doctorate in physical organic chemistry from New York University, where his research involved the design and fabrication of single molecule magnets, chiral molecular switches and self-assembling nano-architectures. In 2006, he founded Nanometics LLC and is the principal investigator on two small business innovation research awards from the National Institutes of Health. In addition, he is a visiting scholar at the Albert Einstein College of Medicine and New York University. As founder and CEO at Nanometics, he leads the research team in designing novel small molecules, polymers and materials for the personal care and pharmaceutical markets.

Biography: Michael Isaacman, PhD, Nanometics, LLC

Michael Isaacman, PhD, graduated from the University of California, Santa Barbara. His research focuses on the synthesis and self-assembling dynamics of silicone-based amphiphilic block copolymers. As an expert in silicone chemistry, he has pioneered novel methodologies for the design and fabrication of silicone polymers for use in drug delivery and personal care. A consultant for the personal care and pharmaceutical industry, he has published in the fields of natural product synthesis, pollutant metal detection and polymer chemistry.

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