We have isolated from venomous snails (Conus geographus and Conus magus) small peptides that block the acetylcholine receptor of vertebrate skeletal muscle. These Alpha-conotoxins have been synthesized chemically in fully active form, being only 13-15 amino acids in length. We plan to extend our work on these toxins, for purposes of increasing our understanding of the receptor's function, and of differences among receptors from various tissues, such as central nervous system and skeletal muscle. To those ends we shall prepare novel forms of the toxins using solid-phase peptide synthesis, and study both their conformations and biological activities. In this way we should be able to exert great control over the molecule's properties, and to correlate those properties with particular structural features. It seems very likely that we shall find variants that bind preferentially to receptors in the CNS rather than skeletal muscle, and shall proceed logically towards toxins with increasing discrimination. Given the versatility of solid-phase peptide synthesis we shall attempt to build molecules having photolabile reactive groups in various positions. We have already demonstrated successful production of homogeneous radiolabeled toxins of high biological activity. Conformational studies will be carried out by high resolution (500 MHz) proton and 13C magnetic resonance. There are unique features of the peptides which are of particular interest in relation to folding - two disulphide bridges create limit flexibility to the extent that different conformers have been separated chromatographically.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034913-05
Application #
3286789
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1985-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1991-03-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Arts and Sciences
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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