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Healthy and Toxic Peptides - Which Peptides Are Bad for Skin?



by Dr. Loren Pickart
BA, Chemistry and Mathematics, University of Minnesota
PhD, Biochemistry, University of California, San Francisco

Discoverer of GHK-Cu and many of the effects of copper peptides

Not all peptides are safe, many are toxic. Since various types of toxicity often take years to manifest, such as linking smoking and cancer, it is essential that any peptide used to create a copper peptide have long term evidence of safety.

 

HEALTHY PEPTIDES:

The use of GHK-Cu has been intensively studied and effective dermal dosages determined. No negative effects have ever been observed at any reasonable dosage up to and over 3% GHK-Cu.

Our second generation copper peptides use peptides from soybean proteins that have been broken down and used for intravenous feeding of hospital patients for many decades. They are very safe.

Dermatologist Howard Maibach (+3,000 papers and +100 books on skin) published four papers on our second generation copper peptides (using the product BioHeal) on humans with various types of experimental human skin injuries and all the results were health positive in terms of a better looking skin.

Zhai, M. D., et al. "Stripped skin model to predict irritation potential of topical agents in vivo in humans." International Journal of Dermatology 37.5 (1998): 386-389.

Zhai, H., Y-H. Leow, and H. I. Maibach. "Human barrier recovery after acute acetone perturbation: an irritant dermatitis model." Clinical and Experimental Dermatology 23.1 (1998): 11-13.

Zhai, Hongbo, Nicholas Poblete, and Howard I. Maibach. "Sodium lauryl sulphate damaged skin in vivo in man: a water barrier repair model." Skin Research and Technology 4.1 (1998): 24-27.

Zhai, Hongbo, et al. "In vivo nickel allergic contact dermatitis: human model for topical therapeutics." Contact Dermatitis 40.4 (1999): 205-208.

 

 

TOXIC PEPTIDES:

Many toxic peptides act rapidly. But a greater danger is the long term use of even very mildly toxic peptides that have very no long term evidence of safety.

 

1. Arginine-rich membrane-permeable peptides are seriously toxic.
Li Q1, Xu M, Cui Y, Huang C, Sun M. Pharmacol Res Perspect. 2017 Oct;5(5).

The membrane-permeable peptides (MPP) such as undecapeptides TAT (YGRKKRRQRRR) and CTP (YGRRARRRRRR) have been receiving much attention for delivering various kinds of low membrane-permeability materials in vitro and in vivo. We have successfully used MPP in carrying various proteins through blood-brain barrier (BBB) in treatment of many kinds of nervous diseases. However, people always concentrate their mind on the efficacy and the mechanism of permeation of the conjugates across BBB, but overlook the toxicity of the membrane-permeable peptide itself.

Once we injected intravenously not very large amounts of gamma-aminobutyric acid-MPP (GABA-MPP) to the mice, to our great surprise, the mice died within seconds with seizure, whereas the GABA control mice well survived. Thus, the importance of the toxicity of MPPs and their conjugates comes into the field of our vision. The low LD50 values of arginine-rich TAT (27.244 mg kg-1 ) and CTP (21.345 mg kg-1) per se in mice indicate that they all fall within the range of highly toxic chemicals. Among the arginine-rich peptides, R11 (RRRRRRRRRRR), a peptide composed purely of arginine residues, has the lowest LD50 value (16.5 mg kg-1) and manifests the highest toxicity, whereas TD (ACSSSPSKHCG), a peptide without arginine residue, shows a much lower toxicity and higher survival rate in mice. The mass percentage of arginine-rich MPP in the conjugate is critically important, the mass radio of arginine in the MPP appears a linear correlation with the toxicity. Thus we conclude, the arginine-rich MPPs are more suitable for using in the macro-molecular conjugates, but not in the small-molecular one.

 


 

2. Toxicity of Biologically Active Peptides and Future Safety Aspects: An Update.
Khan F, Niaz K, Abdollahi M., Curr Drug Discov Technol. 2018;15(3):236-242. 0–44

Peptides are fragments of proteins with significant biological activities. These peptides are encoded in the protein sequence. Initially, such peptides are inactive in their parental form, unless proteolytic enzymes are released. These peptides exhibit various functions and play a therapeutic role in the body. Besides the therapeutic and physiological activities of peptides, the main purpose of this study was to highlight the safety aspects of peptides. We performed an organized toxicity and search of available literature using PubMed, Google Scholar, Medline, EMBASE, Reaxys and Scopus databases. All the relevant citations including research and review articles about the toxicity of biologically active peptides were evaluated and gathered in this study. Biological peptides are widely used in the daily routine ranging from food production to the cosmetics industry and also they have a beneficial role in the treatment and prevention of different diseases.

These peptides are manufactured by both chemical and biotechnological techniques, which show negligible toxicity, however, some naturally occurring peptides and enzymes may induce high toxicity. Depending upon the demand and expected use in the food or pharmaceutical industry, we need different approaches to ascertain the safety of these peptides preferentially through in silico methods. Intestinal wall disruption, erythrocytes and lymphocytes toxicity, free radical production, enzymopathic and immunopathic tissue damage and cytotoxicity due to the consumption of peptides are the main problems in the biological system that lead to various complicated disorders. Therefore, before considering biologically active peptides for food production and for therapeutic purpose, it is first necessary to evaluate the immunogenicity and toxicities of peptides.

 


 

3. Toxic peptides occur frequently in pergid and argid sawfly larvae.
Boevé JL, Rozenberg R, Shinohara A, Schmidt S., PLoS One. 2014 Aug 14;9(8)

Toxic peptides containing D-amino acids are reported from the larvae of sawfly species. The compounds are suspected to constitute environmental contaminants, as they have killed livestock grazing in areas with congregations of such larvae, and related larval extracts are deleterious to ants. Previously, two octapeptides (both called lophyrotomin) and three heptapeptides (pergidin, 4-valinepergidin and dephosphorylated pergidin) were identified from three species in the family Pergidae and one in Argidae.

Here, the hypothesis of widespread occurrence of these peptides among sawflies was tested by LC-MS analyses of single larvae from eight pergid and 28 argid species, plus nine outgroup species. At least two of the five peptides were detected in most sawfly species, whereas none in any outgroup taxon. Wherever peptides were detected, they were present in each examined specimen of the respective species. Some species show high peptide concentrations, reaching up to 0.6% fresh weight of 4-valinepergidin (1.75 mg/larva) in the pergid Pterygophorus nr turneri. All analyzed pergids in the subfamily Pterygophorinae contained pergidin and 4-valinepergidin, all argids in Arginae contained pergidin and one of the two lophyrotomins, whereas none of the peptides was detected in any Perginae pergid or Sterictiphorinae argid (except in Schizocerella pilicornis, which contained pergidin). Three of the four sawfly species that were previously known to contain toxins were reanalyzed here, resulting in several, often strong, quantitative and qualitative differences in the chemical profiles. The most probable ecological role of the peptides is defense against natural enemies; the poisoning of livestock is an epiphenomenon.

 


 

4. Amyloid peptides are toxic via a common oxidative mechanism.
D Schubert, C Behl, R Lesley, A Brack, R Dargusch, Y Sagara, and H Kimura PNAS March 14, 1995, 92 (6) 1989-1993.

Beta-Amyloid protein (A beta) is a member of a small group of proteins that accumulate as amyloid deposits in various tissues. It has recently been demonstrated that the toxicity of A beta toward some neural cells is caused by oxidative damage. Since all of the amyloid diseases are characterized by protein deposited in the antiparallel beta-sheet conformation, it was asked whether there is a common toxic mechanism. It is shown here that the protein components of other human amyloidoses, including amylin, calcitonin, and atrial natriuretic peptide, are all toxic to clonal and primary cells. The toxicity is mediated via a free radical pathway indistinguishable from that of A beta. Experiments with synthetic peptides suggest that it is the amphiphilic nature of the peptides generated by their beta structure rather than their beta structure per se that causes toxicity. These results tend to rule out the alternative that amyloid toxicity is exclusively mediated via specific cell surface receptors.

 


 

5. Aggregation of liposomes induced by the toxic peptides Alzheimer’s Aβs, human amylin and prion (106–126): facilitation by membrane-bound GM1 ganglioside.
Boris Kurganova, Michael Dohb, Nelson Arispeb, Peptides, Volume 25, Issue 2, February 2004, Pages 217-232

To compare both the peptide molecular self-aggregation and the interaction with membrane lipids of the Alzheimer’s amyloid β (Aβ)40, Aβ42 peptides, and the cytotoxic peptides human amylin and prion (106–126) peptides, we applied a liposome aggregation technology. The kinetics of the changes in the optical density (ΔOD) of liposome suspensions generated by the aggregation of liposomes induced by these peptides, allowed us to comparatively analyze their phospholipid affinity and self-aggregation. The kinetic curves showed an initial nonlinear region where d(ΔOD)/dt followed first order kinetics corresponding to the binding of the peptides to the membrane of the liposome, a linear region where d(ΔOD)/dt was constant, corresponding to the interaction between two membrane-bound peptide molecules, and a final slower increasing nonlinear region that corresponds to nucleation or seeding of aggregation.

The analysis of the aggregation curves demonstrated that amylin and prion peptides also showed affinity for the acidic phospholipid phosphatidylserine (PS), as it has previously been shown for the Alzheimer’s Aβ40, Aβ42 peptides. Aβ42 showed the highest, and amylin the lowest, affinity for the  iposome membrane. When bound to the membrane of the liposomes, all the peptides preserved the self-aggregation characteristics observed in solution. Aging the Aβ40 and Aβ42 peptide solutions that permit molecular self-aggregation reduced their capacity to induce liposome aggregation. The self-aggregation of membrane-bound prion molecules was several orders of magnitude higher than that observed for the other toxic peptides. Incorporation of the ganglioside GM1 into the membrane of liposomes enhanced the peptide-induced liposome aggregation. Kinetic analysis revealed that this enhancement was due to facilitation of the formation of bridges between membrane-bound peptide molecules, demonstrating that the peptide–membrane interaction and the peptide amyloidogenesis are independent functions performed at separate molecular regions.

 


 

6. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells.
Wen Yang, John R. Dunlap, Richard B. Andrews, Ronald Wetzel, Human Molecular Genetics, Volume 11, Issue 23, 1 November 2002, Pages 2905–2917.

A number of observations point to the aggregation of expanded polyglutamine [poly(Q)]-containing proteins as playing a central role in the etiology of Huntington's disease (HD) and other expanded CAG-repeat diseases. Transfected cell and transgenic animal models provide some of this support, but irrefutable data on the cytotoxicity of poly(Q) aggregates is lacking. This may be due in part to difficulties in observing all aggregated states in these models, and in part to the inability to conclusively rule out the role of monomeric states of the poly(Q) protein. To address these questions, we produced aggregates of simple poly(Q) peptides in vitro and introduced them to mammalian cells in culture. We find that Cos-7 and PC-12 cells in culture readily take up aggregates of chemically synthesized poly(Q) peptides. Simple poly(Q) aggregates are localized to the cytoplasm and have little impact on cell viability. Aggregates of poly(Q) peptides containing a nuclear localization signal, however, are localized to nuclei and lead to dramatic cell death. Amyloid fibrils of a non-poly(Q) peptide are non-toxic, whether localized to the cytoplasm or nucleus. Nuclear localization of an aggregate of a short, Q20, poly(Q) peptide is just as toxic as that of a long poly(Q) peptide, supporting the notion that the influence of poly(Q) repeat length on disease risk and age of onset is at the level of aggregation efficiency. The results support a direct role for poly(Q) aggregates in HD-related neurotoxicity

 


 

7. Peptide toxins from Conus geographus venom.
Gray, W. R., Luque, A., Olivera, B. M., Barrett, J., & Cruz, L. J. (1981). Peptide toxins from Conus geographus venom. Journal of Biological Chemistry, 256(10), 4734-4740.

The biochemical characterization of three highly toxic peptides from the venom of the marine snail Conus geographus is described in this report. These peptides cause their potent activity by inhibition of the postsynaptic terminus of the vertebrate neuromuscular junction. The relatively small size of the peptides (13-15 amino acids) as well as the polymorphism in their structure makes them potentially attractive probes for synaptic transmission events. The Conus snails are venomous predators that immobilize their prey by a highly specialized venom apparatus.

 


 

8. A rational nomenclature for naming peptide toxins from spiders and other venomous animals.
King, G. F., Gentz, M. C., Escoubas, P., & Nicholson, G. M. (2008). Toxicon, 52(2), 264-276.

Molecular toxinology research was initially driven by an interest in the small subset of animal toxins that are lethal to humans. However, the realization that many venomous creatures possess a complex repertoire of bioactive peptide toxins with potential pharmaceutical and agrochemical applications has led to an explosion in the number of new peptide toxins being discovered and characterized. Unfortunately, this increased awareness of peptide-toxin diversity has not been matched by the development of a generic nomenclature that enables these toxins to be rationally classified, catalogued, and compared. In this article, we introduce a rational nomenclature that can be applied to the naming of peptide toxins from spiders and other venomous animals.

 


 

9. Purification of toxic peptides and the amino acid sequence of CSTX-1 from the multicomponent venom of Cupiennius salei (Araneae: Ctenidae).
Kuhn-Nentwig, L., Schaller, J., & Nentwig, W. (1994). Toxicon, 32(3), 287-302.

The venom of the wandering spider Cupiennius salei was analysed biochemically by gel filtration, cation exchange chromatography, RP-HPLC, IEF, SDS-PAGE and TLC-electrophoresis. The native venom contains high levels of Na+, K+, Ca2+, histamine and taurine. It shows considerable activity of hyaluronidase, but no proteolytic activity. Thirteen peptides (CSTX-1 to CSTX-13) with an apparent mol. wt between 2.6 and 12.5 kDa causing differently strong toxic effects were purified. Toxicity data of the crude venom (insects and mouse) are given and compared with the toxicity of CSTX-1, which causes most of the crude venom's toxicity. CSTX-1 has a mol. wt of 8352.6 and its amino acid sequence of 74 amino acids is given.

 


 

10. An overview of peptide toxins from the venom of the Chinese bird spider Selenocosmia huwena Wang [= Ornithoctonus huwena (Wang)].
Liang, S. (2004). Toxicon, 43(5), 575-585.

The bird spider Selenocosmia huwena Wang [=Ornithoctonus huwena (Wang)] is one of the most venomous spiders in China. The venom of this spider contains a mixture of compounds with different types of biological activity. About 400 proteins and peptides from the venom can be separated and detected by 2D electrophoresis. Of these, 14 peptide toxins have been purified and characterized from the venom of this spider, with several peptide toxins exhibiting structural similarity but high functional diversity. Most of these huwentoxins (HWTX) contain 30–40 amino acids with three disulfide bonds and adopt an ‘inhibitor cystine-knot’ (ICK) motif in their three dimensional structure, except for huwentoxin-II (HWTX-II) which adopts a novel scaffold different from the ICK motif. As a group, the toxins possess quite different biological activities including inhibition of voltage-gated calcium and sodium channels, insecticidal activity, lectin-like agglutination, and inhibition of trypsin. Eight cDNAs encoding seven toxins, HWTX-I, -II, -III, -IIIa, -IV -V, and, -VII and one lectin, S. huwena lectin-I (SHL-I), have been cloned and sequenced. Comparison of the cDNA sequences of the eight peptides from S. huwena indicates that they can be classified into two different superfamilies according to the ‘prepro’ region of their cDNA sequences.



 

We could add hundreds more references on toxic peptides, but you get the idea...

Questions? Email Dr. Pickart directly at: drlorenpickart@gmail.com

 

 

 

READ MORE on our page What Are True Copper Peptides - Avoid the Unproven