Conotoxins tools for pharmacological enhancement. The focus on this

Conotoxins have
received a great deal of attention as promising novel leads in drug
development. These types of peptides can target a wide range of neurological
ion channels and membrane-bound receptors. This study explores the stabilization of a novel a-conotoxin
in Conus virgo by using
hydroxyprolines and cyclization as tools for pharmacological enhancement. The
focus on this specific a-conotoxin is due to its unique three
potential sites for hydroxylation with proline. Hydroxyprolines and cyclization
have been observed to augment the stabilization of peptides, to reduce enzymatic
degradation, and to promote increased bioavailability – a highly prized
pharmaceutical characteristic. However, ‘conopeptides’ cannot be
orally active therapeutic agents because enzymes degrade their backbone in the
gastrointestinal tract. For example, Ziconotide, derived from w-conotoxin
MVIIA of Conus magus, is a
satisfactory analgesia given only through the spine. In this specific research,
a-conotoxins are one of the few venoms capable of paralyzing
polychete worms by particularly inhibiting the a3b2 acetylcholine subtype. By utilizing
this anthelmintic drug concept, potentially bioengineering a-conopeptide
drugs can naturally and specifically help parasitic diseases such as the prevalent
rat lungworm in Hawaii. Thus, our objective is to seek an alternative to spinal
injections and to broad-spectrum synthetic drugs. We will use the techniques of
reversed-phase high-pressure liquid chromatography, mass spectrometry,
oxidation reactions, virgo-fluorophore conjugates, and bioactivity by LD50
with receptor assays in swordtails (Xiphophorus
hellerii) to assess production and bioactivity of our peptide
candidates. We expect to be
able to influence the stability of this a-conotoxin with hydroxyprolines and
cyclization while continuing to elucidate the pharmacological limitations in
peptide drug design.


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