Ziconotide: Molecular Structure

Molecular Structure#

Ziconotide (omega-conotoxin MVIIA) is a 25-amino acid peptide with the molecular formula C102H172N36O32S7 and a molecular weight of 2639.14 Da. The peptide is derived from the venom of Conus magus, a fish-hunting cone snail that uses calcium channel-blocking peptides to immobilize prey.

Amino Acid Sequence#

The complete sequence is CKGKGAKCSRLMYDCCTGSCRSGKC-NH2. The peptide contains six cysteine residues that form three intramolecular disulfide bonds in a specific pattern: Cys1-Cys16, Cys8-Cys20, and Cys15-Cys25. This disulfide connectivity creates an inhibitor cystine knot (ICK) motif, a structural framework found in many venom-derived ion channel blockers across species.

Chemical Properties#

The ICK motif consists of a ring formed by two disulfide bonds (Cys1-Cys16 and Cys15-Cys25) and the intervening backbone, through which the third disulfide bond (Cys8-Cys20) passes. This knot structure confers exceptional stability to the peptide, making it resistant to thermal and proteolytic degradation compared to linear peptides.

The C-terminal amidation is important for biological activity. The peptide carries a net positive charge at physiological pH due to multiple lysine and arginine residues, which contributes to its interaction with the negatively charged vestibule of the calcium channel.

Pharmacokinetic Properties#

Following intrathecal administration, ziconotide has a cerebrospinal fluid (CSF) half-life of approximately 4.6 hours. Systemic exposure is minimal due to rapid clearance from plasma (mean plasma half-life approximately 1.3 hours). The volume of distribution in the CSF approximates CSF volume (approximately 140 mL). Ziconotide is metabolized by endopeptidases and exopeptidases present in various organs and does not appear to be metabolized by cytochrome P450 enzymes.

Stability Characteristics#

The disulfide-stabilized ICK structure provides ziconotide with greater stability than most linear peptides. However, the commercial formulation (Prialt) must be stored refrigerated at 2-8 degrees C and protected from light. Reconstituted solutions in preservative-free normal saline should be used within 24 hours at room temperature or 60 days at 2-8 degrees C when stored in an external microinfusion pump.

Molecular Context#

Ziconotide belongs to the Pain category of research peptides. The molecular properties of Ziconotide determine its pharmacological behavior, including receptor binding, distribution, metabolism, and elimination. Understanding these properties is fundamental to interpreting clinical data and designing research protocols.

Structural Overview#

Ziconotide is characterized as: Ziconotide is a 25-amino acid peptide with a molecular weight of 2639.14 Da and the molecular formula C102H172N36O32S7. It contains three disulfide bonds (Cys1-Cys16, Cys8-Cys20, Cys15-Cys25) that form an inhibitor cystine knot (ICK) motif, a structural framework common to many ion channel-blocking toxins. The C-terminus is amidated. The disulfide-stabilized structure is essential for high-affinity binding to N-type voltage-gated calcium channels (Cav2.2)..

Amino Acid Sequence Details#

The amino acid sequence of Ziconotide is: CKGKGAKCSRLMYDCCTGSCRSGKC-NH2. This sequence determines the peptide's three-dimensional structure, receptor binding properties, and biological activity.

Pharmacokinetic Profile#

Half-Life: 4.6 hours (CSF)

The half-life of a peptide influences dosing frequency, duration of effect, and the clinical utility of the compound. Researchers should consider the half-life when designing experimental protocols.

Related Reading#

• Ziconotide overview and research guide
• Peptides similar to Ziconotide
• Ziconotide research evidence