Mimicking protein surfaces with cyclic peptides: w-conotoxin GVIA mimics as novel analgesic and neuroprotective agents

Funding Activity

Website
http://purl.org/au-research/grants/nhmrc/120402

Funding Status
Closed

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Funded Activity Summary

The omega-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, omega-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered to the CNS via an intrathecal catheter, MVIIA and GVIA are analgesic in acute, chronic and neuropathic pain models, and protective following ischaemia-induced neuronal injury, such as occurs following stroke. They do not suffer from the development of tolerance, in contrast with the opioids, such as morphine, which lose their analgesic potency over time and have undesirable side effects. We have determined the three-dimensional structure of GVIA and mapped onto that structure its calcium channel binding surface. This information is a starting point for the structure-based design of truncated and stabilised peptidic analogues of GVIA, which should have several advantages over the native polypeptides as candidates for the treatment of chronic pain and ischaemia-induced neuronal damage. In the course of this work we shall also generate a range of libraries of experimentally determined and predicted structures based on small, cyclic peptides. These libraries will be valuable tools for mimicking key functional regions of protein surfaces in small molecules that are easily (and cheaply) synthesised and have potentially favourable bioavailability. Thus, this project will also increase our understanding of the attributes of small cyclic peptides as mimics of functionally important protein surfaces and provide valuable tools for the design and evaluation of such peptides.

Funded Activity Details

Start Date: 01-01-2000

End Date: 01-01-2002

Funding Scheme: NHMRC Project Grants

Funding Amount: $216,412.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Biochemistry And Cell Biology Not Elsewhere Classified

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

Calcium channel blockade | Cancer | Chronic pain | Ischaemic injury | Neuropathy | Peptide design | Peptide libraries | Polypeptide toxin | Stroke | Structure determination

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