Antisense Peptide Research

Jonathan Heal (e-mail:j.heal@ic.ac.uk)
2nd year PhD student - Antisense Peptide Chemistry


My work concerns trying to find novel approaches to tackle Alzheimers disease (AD). AD is a devastating neurological disorder of enormous socio-economic impact. One of the primary causes of AD is the overexpression, followed by proteolysis, of proteins of the Amyloid Precursor Protein (APP) family which leads to the formation of toxic b-amyloid-containing neuritic plaques. We have been investigating ways to regulate the overexpression of APP's and thereby come up with a lasting treatment for this terrifying disease by controlling the amyloid-cascade leading to the formation of neuritic plaques. There is now a considerable body of evidence indicating the involvement of the inflammatory response in AD pathogenesis. In fact, there is much evidence now available which suggests that the pro-inflammatory cytokines (Interleukin-1a [IL-1a], Interleukin-1b [IL-1b] and Interleukin-6 [IL-6]) play a key role in promoting the overexpression of APP's in the brains of AD patients. Therefore, highly selective antagonists to these cytokines could be potent anti-AD compounds.

We developed a novel way to antagonise both IL-1a and IL-1b, using antisense peptides designed to target a specific surface loop present in both IL-1a and IL-1b but not in the natural antagonist Interleukin-1 receptor antagonist (IL-1ra). The antisense peptide was designed by deriving the antisense DNA code of the IL-1b surface loop and deducing the corresponding antisense peptide sequence by translating the antisense DNA code in the 5'®3' direction. Two antisense peptides were synthesised and shown to inhibit both IL-1a and IL-1b. This is not the first time that antisense peptides have been shown to interact with their corresponding sense peptides but this is certainly the first time, to the best of our knowledge, that purpose-designed antisense peptide "mini-receptor" inhibitors have been described. If you don't believe this, have a look at the paper below!

I am now trying to understand the antisense peptide phenomenon and extend our approach to try and antagonise other parts of the inflammatory amyloid-cascade process of AD.



Recent Publications

J. W. Davids, A. El-Bakri, J. Heal, G. Christie, G. W. Roberts, J. G. Raynes & A. D. Miller, Design of antisense (complementary) peptides as selective inhibitors of cytokine interleukin-1,
Angew. Chem. Intl. Ed. Engl., 1997, 36, 962; Angew. Chem., 1997, 109, 999


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