Improving a peptide targeting TDP-43 with bioinformatics tools.

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Searching for a TDP-43 therapy

Genetic therapies against TDP-43 aggregates had been proposed for ALS disease.

While this is certainly feasible with the current state of art (see my book), it would certainly be sold at a cost similar to Zolgensma, because of the lack of competition in the field.

The classical drug which complies with the "Pfizer rule of five" is a peptide, so a peptide that would remove TDP-43 would be desirable. Peptides are low cost and easy to procure.

Improving an already published peptide

Several scientific articles [0] are suggesting that a peptide might help in ALS by removing TDP-43 from mitochondria.

YGRKKRRQRRRAQFPGACGL

The initially proposed peptide was formed by assembling a M1 section from TDP-43 with a TAT peptide.
* The M1 section is: FPGACGL
* The M3 section is: GFGFV
* Tat is a regulatory protein that drastically enhances the efficiency of viral transcription, for example in HIV with a transition to the most dangerous form of AIDS (T-tropic).

Bioinformatics tools suggest that its biological function as a neurotoxin which blocks acetylcholine receptors. While a patent was written in 2016 (and still valid for 2019) the main scientist of the team who wrote the 2016 article, said later that this peptide was actually very toxic. This statement is not difficult to trust.

An improved peptide

If we use a peptide made simply with an altered M3 section followed by the M1 section.

Some of those peptides, are predicted by bioinformatics tools has not being a toxin, and not an antigen.

Those peptides seems to have all required qualities: * They must not be toxic * They must go through the BB barrier * They must localize in the mitochondria (where it is supposed to help remove TDP-43)

The best seems to be this one: Peptide sequence: GFGFVRPGACGL Smiles: NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)N[email protected]@(C(C)C)C(=O)N[email protected]@(CCCNC(=N)N)C(=O)N1[email protected]@(CCC1)C(=O)NCC(=O)N[email protected]@(C)C(=O)N[email protected]@(CS)C(=O)NCC(=O)N[email protected]@(CC(C)C)C(=O)O However it does not terminate entirely with FPGACGL, so it might be prudent to use also the next one below.

Peptide sequence: GFGFPFPGACGL Smiles: NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)NCC(=O)N[email protected]@(Cc1ccccc1)C(=O)N1[email protected]@(CCC1)C(=O)N[email protected]@(Cc1ccccc1)C(=O)N1[email protected]@(CCC1)C(=O)NCC(=O)N[email protected]@(C)C(=O)N[email protected]@(CS)C(=O)NCC(=O)N[email protected]@(CC(C)C)C(=O)O

Maximum Recommended Daily Dose (Human): 0.00124 (mmol/kg-bw/day) / 1.45 (mg/kg_bw/day)

This is not a medical advice, it is just a theoretical exercise, to see which peptide could be a candidate to offer the effect described in the following article: https://www.nature.com/articles/nm.4130

Tool for testing neurotoxin function:
https://webs.iiitd.edu.in/raghava/ntxpred
Tool for testing immunogenicity:
http://www.ddg-pharmfac.net/vaxijen/
Blast on human genome:
https://blast.ncbi.nlm.nih.gov/Blast.cgi
http://tox.charite.de/protox_II/index.php?site=faq
http://lmmd.ecust.edu.cn/admetsar2

[0] Including: The Inhibition of TDP-43 Mitochondrial Localization Blocks Its Neuronal Toxicity Article in Nature medicine · June 2016 DOI: 10.1038/nm.4130

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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