The mollusks use a deadly dose of conotoxins (peptide toxins, e.g., α/ω-conotoxin peptides) that disrupt myriad biological functions. The mollusks inject into passing prey with hypodermic-needle-like teeth that shoot from their mouths like harpoons.
Within the conotoxin brew are several peptides that relieve tough-to-treat neuropathic pain just as well as morphine does but without its addictive properties. Although scientists have tried to turn such compounds into pain relievers, they've been hamstrung with problems administering such drugs. The pain reliever Prialt (see structure, Ziconotide), a synthetic version of ω-conotoxin MVIIA, but it must be injected directly into the spinal cord with a surgically implanted pump.
Now interestingly, scientists in Australia lead by Prof. David Craik (Institute for Molecular Bioscience at the University of Queensland), have managed to engineer a conotoxin that can be taken orally. Researchers found that, by linking the N-terminus of α-conotoxin Vc1.1—a compound derived from Conus victoriae—to its C-terminus, they could make the 16-residue peptide orally active. In the cyclized peptide, which is known as α-conotoxin cVc1.1, the protein's head and tail are tethered by a string of six amino acids—two alanines flanked on each side by two glycines. Prof. Craik says he chose the linker because it was inexpensive, wouldn't add any functionality to the molecule, and would be easy to characterize with nuclear magnetic resonance. In tests with rats, the cyclized peptide proved to be as potent a painkiller as gabapentin, the most popular drug for neuropathic pain, even though the conotoxin-based peptide was administered at a dose that is less than 1% of the dose typically given for gabapentin (other orally prescribed peptide is Ciclosporin a immunosuppressant).
Craik's group has shown that cyclizing larger peptides can make them orally available. His team's analysis of the protein database shows that up to 25% of all proteins have their ends within 10 Å of one another a distance that could easily be spanned with linkers of six to 10 amino acids.
"All you need is for the ends to be roughly close to one another," Prof. Clark says.
Craik says the cyclization also enhances hydrogen bonding across the entire molecule, making it resistant to the endopeptidases that attack a protein's interior amino acids. He says it's sort of like a zipper: "A zipper can be regarded as a series of hydrogen bonds all interlocking together, and when you zip it all up, you've got a beautiful set of coordinated hydrogen bonds. But you've still got two ends, and when you pull apart those two ends of the zipper, then the first hydrogen bond goes, then the next, and then the next. Craik has discovered several other examples of cyclic peptides, which he calls cyclotides (C&EN, April 19, 2004, page 40). He's hoping to use their structural features to guide the engineering of other peptides, as he did with α-conotoxin cVc1.1 At the moment, Craik is trying to raise funds so enough preliminary experiments can be done to file an Investigational New Drug Application. "The most challenging aspect has been just raising the money to get it commercialized," he says. "Pharmaceutical companies are always a little nervous about peptides. We need more success stories so that they'll see peptides not only as fantastic leads but also as potential drugs."...
Ref : http://www3.interscience.wiley.com/journal/123500852/abstract
