Bell Eapen MD, PhD.

Bringing Digital health & Gen AI research to life!

The great anti-ageing mantra

Matrix metalloproteinases (MMPs) are important in dermatology as they are involved in remodelling extracellular matrix (ECM). It is a big family of enzymes, all having a common domain structure with a pro-peptide region, catalytic domain, hinge region and the haemopexin-like C-terminal domain.  They are involved in a variety of biological functions. MMP1 is involved in the premature ageing in smokers.[1] Inhibition of certain MMPs have anti-ageing effect while inhibition of others promote hyperproliferative disorders and scars. However because of the structural similarities, rational design of specific inhibitors are very difficult. Most of the rationally designed MMP inhibitors like  marimastat (BB-2516) and  cipemastat (Ro 32-3555) have performed poorly in clinical studies.

This is a Graph showing the mutual activation ...
This is a Graph showing the mutual activation of matrix metallo-proteinases. (Photo credit: Wikipedia)

This paper [2] proposes a new approach wherein regulatory sites hidden and scattered over different locations on the protein’s surface are targeted instead of the catalytic site using specially designed branched amphiphilic molecules. They have demonstrated that MMP family possess a unique set of such sites making it possible to target specific MMPs without affecting others. If this technology can be successfully developed it may have several applications including many dermatological uses.

References:

1. Lahmann, Christine et al. “Matrix metalloproteinase-1 and skin ageing in smokers.” The Lancet 357.9260 (2001): 935-936.

2. Udi, Yael et al. “Unraveling hidden regulatory sites in structurally homologous metalloproteases.” Journal of Molecular Biology (2013).

Published by Bell Eapen on | Permalink

Best peptides for women

In continuation with my previous posts here and in skin deep, let me add few more things I found recently.

Peptide Synthesis Deprotection
Peptide Synthesis Deprotection (Photo credit: Beige Alert)

The article titled “Systematic Discovery of New Recognition Peptides Mediating Protein Interaction Networks “ published recently in PLOS Biology ( full text at : http://dx.plos.org/10.1371/journal.pbio.0030405 ) describes the signalling by short peptide segments. Short peptide segments interact with globular protein domains that share a common sequence pattern (e.g., SH3 binding to PxxP). They also point out that sequence comparison experiments are unlikely to discover the optimum short motif. They recommend using data from genome-scale interaction studies. So the methodology adopted by the designers of peptide-21 may not be robust.

OK, now I am going to do something here that I rarely ever do on my blogs: I am going to shamelessly self promote me without actually giving away much information. My plan is to get noticed by the cosmetic tycoons and make some money out of this incessant babbling about beauty peptides 🙂

English: Example of mechanism of direct penetr...
English: Example of mechanism of direct penetrating peptide (Photo credit: Wikipedia)

I used a newly published algorithm (not mine) for bioinformatics analysis and found some interesting information.

The most commonly occurring tetra peptide in collagen is in fact GXXG and PXXP the commonest being GPPG.

The commonest tetra peptide repeats were GERG, GEKG, GFPG, GENG, GPRG, GHRG.

This is what terapeptide-21 is based on and there is nothing new till here.

But here comes the most surprising part!

The highest scoring short peptide of probable biological (signal) function does not belong to the above list!!

Hey, Do I hear my phone ringing?????

Published by Bell Eapen on | Permalink

Beauty born out of Bioinformatics

The beauty and the anti-ageing industry is focused on finding ways to augment the fibrillar proteins collagen and elastin embedded in an extracellular matrix in the dermal layer of the skin. A pentapeptide KTTKS, within the carboxy terminal propeptide of type I collagen is extensively used as an anti-ageing cosmetic ingredient. The proposed mechanism of action is tricking the body into believing that there is excessive collagen degradation so that collagen biosynthetic pathway is stimulated. I have blogged about the potential limitations in Skin Deep .

B0005968 Collagen fibril forming in vitro
B0005968 Collagen fibril forming in vitro (Photo credit: wellcome images)

Yet another peptide called tetrapeptide – 21 is claimed to be superior to KTTKS in anti-ageing properties. They claim to have discovered this by using bioinformatics methodology.

Let me quote from a product brochure:

We used bioinformatic methods to identify highly repetitive amino acid motifs in several human ECM proteins to identify sequences with inherent anti-aging activities.  Using the amino acid sequences of collagen I, II, III, IV, V, elastin, and proelastin, tetra-peptide sequences were identified by their frequency of occurrence. 

Beauty box1886
Beauty box1886 (Photo credit: Wikipedia)

The methodology has never been published. Their patent application states that they found GXXG and PXXP as the common motif among all collagens and elastin. They tried various combinations and found GEKG as the most biologically active one. At the sequence level all collagens are quite similar. It is also well known that the most common motifs in all types of collagen is GPX. So finding GXXG as the commonest tetrapeptide motif is hardly surprising.

So dear biochemicians:

1. Where does the MMPs cleave collagen?
2. How many amino acid residues are there in collagen degradation fragments?
3. Do you think GXXG can mimick collagen fragment?

and dear bioinformaticians:
1. If we consider Collagen I & III into consideration (more relevant for skin) which are the commonest penta and hexa peptide motifs. Do they converge?

Susan Anton
Susan Anton (Photo credit: Wikipedia)

2. How does adding an H to the carboxy terminal of such a penta/hexapeptide affect the polarity? Will it increase the skin penetration as described here? http://www.ncbi.nlm.nih.gov/pubmed/22452335

and finally dear cell biologists:
1. Do all collagen degradation fragments stimulate UVB induced hyaluronic acid degradation as described here: http://www.ncbi.nlm.nih.gov/pubmed/21454612

I have added a wiki page for this to summarise the findings. Feel free to add your thoughts here.

Resources:

collagen alpha-1(I) chain preproprotein [Homo sapiens] : http://www.ncbi.nlm.nih.gov/protein/NP_000079.2

collagen alpha-2(I) chain precursor [Homo sapiens]
http://www.ncbi.nlm.nih.gov/protein/NP_000080.2

collagen alpha-1(III) chain preproprotein [Homo sapiens]
http://www.ncbi.nlm.nih.gov/protein/4502951

Published by Bell Eapen on | Permalink