Chemical synthesis of spider venom could change the way we treat stroke and heart attack
- Post by: CIPPS
- 18 September 2023
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Heart attack and stroke are the leading causes of death worldwide, yet, remarkably, there are no therapeutics available to prevent the tissue injury caused by these life-threatening events. Both diseases occur when a blockage in a blood vessel prevents oxygenated blood from reaching the relevant tissue. The resulting oxygen deprivation causes tissue acidosis, which in turn activates an ion channel known as acid sensing ion channel 1a (ASIC1a). Activation of ASIC1a sets in motion cell death pathways that cause heart muscle cells or brain neurons to die by suicide. There are currently no treatments on the market that prevent activation of these cell death pathways.
In 2017, our CI Glenn King reported that a peptide known as Hi1a found in venom of the K’gari funnel-web spider could inhibit ASIC1a and prevent it activating cell death pathways after stroke. Administration of Hi1a reduced brain injury after stroke and led to better functional recovery. In 2020, King and collaborator Dr Nathan Palpant reported that Hi1a could also protect heart tissue after myocardial infarction by switching off cell death pathways. These exciting results represented an important step towards a change in the way we treat stroke and heart attack. However, there was one significant issue; production of Hi1a. Extracting Hi1a from spiders is an impractical and inefficient process, and bacterial expression produced only low yields of Hi1a. Given the breadth of CIPPS capabilities, chemical synthesis was suggested as an alternate method of Hi1a manufacture for clinical studies.
In 2020 and 2021, CI King and deputy-director Richard Payne collaborated on this project, to develop a robust method for the chemical synthesis of Hi1a. Hi1a is like a chemical puzzle with an added third dimension – the intricate fold of the peptide, posing a great challenge for its synthesis. The peptide is large, comprising 76 amino acid residues and it has a complex structure consisting of two three-dimensional knot-like domains joined by a short linker. Payne and former-PhD student Nisharnthi Duggan designed a synthetic strategy in which the two domains were synthesised via standard solid-phase peptide synthesis and joined by native chemical ligation. This strategy solved the chemical puzzle in two dimensions, however the third dimension had to be solved through peptide folding, a trial-and-error process. After many attempts using a diverse range of folding conditions, the third dimension of the puzzle was solved the intricately folded peptide Hi1a was produced.
To confirm that synthetic Hi1a has the same activity as the native venom peptide, the King lab tested its activity against human ASIC1a. It was shown that the synthetic peptide behaved the same way as the natural peptide, verifying that laboratory synthesis is a suitable method to produce Hi1a for clinical studies. These results were published in Organic Letters in October 2021; the article has received nearly 2000 views since then, with over 20 mentions on Twitter.
This project represents a successful cross-nodal and inter-flagship collaboration between CI King, co-leader of Flagship 1, and deputy-director Payne working across Flagship 3. The project falls within with our Discover and Develop themes. Excitingly, work resulting from this collaboration is being built upon in an Australian biotech company (Infensa Bioscience) recently co-founded by CI King.