If I design a peptide for preventing aggregation of Abeta 42 peptide, what are aspects should I consider if I want to suggest it as drug for Alzheimer disease. What all are the properties should that peptide have? What are all the characterizations should I perform?
Hi there,
It exists now a lot of peptides designed against Amyloid beta, managed to avoid or inhibit agregation; but there is main features you have to manage in my opinion:
Important properties: Beta-breaker, no self-agregation, good clearance, low toxicity, passage through BBB (size, shape)
* First, your peptides need to be a beta-breaker. Some peptides, like KLVFF and derivatives, takes place on Beta sheet structure of Abeta protein. The prob is when you used B-breaker, it is possible to have more oligomers forms, that are more toxic.
* Second, the common technique to obtain useful peptides is phage display. It may be your starting point, because there is also compatible peptides like IFALMG without structural homology; with a good inhibition in vitro. It is probably a good thing to take a look between polarity of peptides and Beta amyloid proteins too.Article Peptides for Therapy and Diagnosis of Alzheimer’s Disease
* Third, your choice of valuable peptide will take in account 4 important axes : high affinity, control of self agregation (ex: HHQKLVFFAED self aggregate in few hours), protection against endogenous protease in vivo, passage through the blood brain barrier.
To avoid in vivo trouble, it may be good to protect your products by some other molecules (by encapsulation, using nanoparticles, quantum dots...), with some limitation of size, shape, concentration and toxicity too. You can do chemical adjustement in other part, like cyclisation that works for protection and stabilisation of peptides:
Article Covalent modifier-type aggregation inhibitor of amyloid-β ba...
So, for the characterisation, the article giving by Sebastian is really useful (thanks for me too by the way!). Finally, to test your products against BBB in vitro, it exists some models.
Article In vitro models of the blood-brain barrier: An overview of c...
I hope this will help you,
best regards,
Jonathan
Hi,
*Aβ generally occurs in various isoforms that differ by the number of residues at the C-terminal end of the peptide. Aβ(1–40), (1–42) . 42 isoforrm is involved in neurodegeneration while 40 isoform is involved in initial disease process. so you must consider on which isoform it is going to act.
*Secondly, amyloid peptides have β-sheet arrangement, so your peptide should be able to break that beta arrangements.
*Third one , it is very difficult to solubilise the amyloid beta, again if you are targeting at 40 isoform it would be easy to dissolve, and if the target is 42 isoform it will be a tough job to solubilise as most of solublising agents themselves contribute in toxiciity and further amyloid peptide are self aggregating and they fill form protofibrils and mature fibrils.
*in my opinion kinetic studies on aggregation of amyloid beta should be carried out as it will you in selecting the appropriate solublising agent for abeta.
* For determining the morphological differences you can do time-resolved thioflavine-T (ThT) fluorescence spectroscopy which is specific for Amyloid beta isoforms, and you can easily distinguish between 40 and 42 isoform.
* Circular dichorism can also bee used for assessing the structural elements.
* Depends on the type of study, whether you will be doing in-vitro or in-vivo
as for majority of invitro studies 40 isoform is used while in in vivo studies 42 isoform is considered to be best for mimicking exact symptoms of AD.
*BBB permeability and DELIVERY (carriers are also unstable, be careful in selecting the carrier for your peptide) are basic things but are of prime importance while designing a peptide.
ALL THE BEST
- Badges
- Science topic
- Similar topics
- Biological Science
- Biochemistry
- Biomolecules
- Peptides