CJC-1295 DAC: Molecular Structure

Molecular Structure#

CJC-1295 DAC is a synthetic peptide-drug conjugate with a total molecular weight of approximately 3,647.28 Da (peptide portion). The molecule consists of two functional components: a modified growth hormone-releasing hormone (GHRH) analog derived from GRF(1-29), and a Drug Affinity Complex (DAC) moiety that enables covalent binding to serum albumin after injection.

The peptide component is based on the first 29 amino acids of human GHRH (also known as growth hormone-releasing factor, GRF), which represent the minimal sequence required for full biological activity at the GHRH receptor. Four strategic amino acid substitutions have been incorporated at positions 2, 8, 15, and 27 to confer resistance to enzymatic degradation, particularly by dipeptidyl peptidase IV (DPP-IV), which rapidly cleaves native GHRH at the Ala2-Asp3 bond.

Amino Acid Sequence#

The modified GRF(1-29) sequence in CJC-1295 is: Tyr-D-Ala-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg.

The key modifications from native GRF(1-29) include: position 2 changed from Ala to D-Ala (protects against DPP-IV cleavage by introducing the unnatural D-amino acid configuration); position 8 changed from Asn to Gln (prevents deamidation, improving stability); position 15 changed from Gly to Ala (enhances metabolic stability); and position 27 changed from Met to Leu (prevents oxidation of the methionine sulfur, improving shelf stability).

A 30th residue, lysine, is appended at the C-terminus and serves as the attachment point for the DAC moiety. The epsilon-amino group of this lysine is conjugated to a maleimidopropionic acid (MPA) linker, which constitutes the reactive component of the Drug Affinity Complex.

Drug Affinity Complex (DAC) Technology#

The Drug Affinity Complex is the defining technological feature of CJC-1295 DAC that distinguishes it from its non-DAC counterpart (also called modified GRF(1-29) or CJC-1295 without DAC). The DAC consists of a maleimidopropionic acid group conjugated to the C-terminal lysine of the peptide.

After subcutaneous injection, the maleimide group of the DAC undergoes a Michael addition reaction with the free thiol group (Cys34) on human serum albumin. This covalent bond formation is rapid and essentially irreversible under physiological conditions. The resulting peptide-albumin conjugate has an effective molecular weight of approximately 70 kDa (albumin contributing approximately 66.5 kDa), which dramatically reduces renal filtration and protects the peptide from proteolytic degradation.

The bioconjugation with albumin is the primary mechanism of half-life extension. Free CJC-1295 without DAC has a plasma half-life of approximately 30 minutes, while the albumin-conjugated form achieves a half-life of 6 to 8 days. This represents an approximately 300-fold increase in circulatory persistence.

Pharmacokinetic Properties#

The pharmacokinetics of CJC-1295 DAC are dominated by the albumin binding kinetics and the long circulatory half-life of the albumin conjugate. After subcutaneous injection, the peptide is absorbed into the systemic circulation and rapidly conjugates with albumin (binding is largely complete within hours).

The apparent half-life of 6 to 8 days reflects the slow dissociation and clearance of the albumin-peptide conjugate. This long half-life results in significant accumulation with weekly dosing, with steady-state plasma levels typically achieved after 2 to 3 weekly doses.

The pharmacodynamic effects (GH and IGF-1 elevation) persist throughout the dosing interval. Following a single subcutaneous injection, IGF-1 levels begin to rise within 24 hours, peak at approximately 48 to 96 hours, and remain elevated above baseline for 6 to 14 days depending on the dose. With weekly dosing, IGF-1 levels show progressive accumulation, typically reaching a new steady state after 2 to 4 weeks.

Chemical Properties#

CJC-1295 DAC is supplied as a lyophilized white powder for research purposes. The peptide is soluble in sterile water and bacteriostatic water. The isoelectric point of the peptide portion is approximately 10.2, reflecting its basic character due to multiple arginine and lysine residues.

The lyophilized form is relatively stable when stored at -20 degrees Celsius, protected from moisture and light. The reconstituted solution is less stable and should be stored refrigerated at 2 to 8 degrees Celsius. The maleimide group in the DAC moiety is reactive and can undergo hydrolysis in aqueous solution over time, which would reduce the albumin-binding efficiency. Therefore, reconstituted solutions should be used promptly.

Comparison with CJC-1295 without DAC#

The critical structural and pharmacological difference between CJC-1295 DAC and its non-DAC counterpart lies in the presence or absence of the maleimidopropionic acid conjugation moiety. CJC-1295 without DAC (also referred to as modified GRF(1-29) or Mod GRF 1-29) contains the same modified peptide sequence but lacks the DAC attachment.

Without the DAC, the peptide cannot bind albumin and retains a short half-life of approximately 30 minutes. This necessitates multiple daily injections (typically 2 to 3 times daily) rather than the weekly dosing possible with CJC-1295 DAC. The shorter half-life of the non-DAC version produces more discrete GH pulses, while the DAC version creates sustained GH elevation with superimposed pulsatility.

Related Reading#

• CJC-1295 DAC overview and research guide
• Peptides similar to CJC-1295 DAC
• CJC-1295 DAC research evidence