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