CJC-1295 DAC

Overview and Mechanism of Action

CJC-1295 with DAC (Drug Affinity Complex) is a synthetic 30-amino-acid analogue of endogenous growth hormone-releasing hormone (GHRH) engineered for dramatically extended plasma half-life through covalent albumin binding. Endogenous GHRH, a 44-amino-acid hypothalamic peptide, stimulates pituitary somatotroph cells to synthesize and secrete growth hormone (GH) by binding to the GHRH receptor (GHRHR), a Gs protein-coupled receptor whose activation elevates intracellular cyclic AMP, activates protein kinase A, and opens voltage-gated calcium channels, triggering GH vesicle exocytosis.

The structural basis of CJC-1295 with DAC begins with the truncated GHRH(1-29) sequence (the minimal fragment retaining full GHRHR activity), which has been modified at four positions to resist proteolytic degradation: substitution of alanine at position 2 with alpha-aminoisobutyric acid (Aib) to block DPP-IV cleavage, glutamine at position 8 with alanine, leucine at position 15 with alanine, and asparagine at position 27 with arginine. These substitutions are shared with the no-DAC variant (Mod GRF 1-29). The defining feature of CJC-1295 with DAC is the additional incorporation of a maleimido-propionamide (MPA) moiety — the Drug Affinity Complex — attached to a lysine residue at the C-terminus of the modified GHRH sequence. The maleimide group reacts selectively with the free thiol of Cys-34 on circulating serum albumin via a Michael addition reaction, forming a stable thioether bond. Since albumin has a plasma half-life of approximately 19 days, this covalent conjugate substantially extends the effective circulating half-life of the peptide from the ~30 minutes of unmodified GHRH analogues to an estimated 6–8 days, enabling weekly or twice-weekly dosing in research protocols.

Research History and Development

The development of GHRH analogues with extended half-life was motivated by the recognition that pulsatile GHRH administration was required to maintain somatotroph responsiveness, and that more convenient dosing intervals would be required for practical clinical research. Cambrex Corporation (later ConjuChem) developed the DAC albumin-binding technology and applied it to a modified GHRH sequence to produce CJC-1295 with DAC. The seminal human pharmacokinetic study, published by Jetté et al. in the Journal of Clinical Endocrinology and Metabolism in 2005, demonstrated that single subcutaneous doses of CJC-1295 with DAC produced sustained, dose-dependent elevations in mean plasma GH concentrations and IGF-1 levels over 6 days, with a pharmacodynamic profile consistent with the extended half-life predicted by the albumin-binding mechanism.

The compound has subsequently been employed in research examining the effects of sustained GHRH receptor stimulation on GH pulsatility, body composition, metabolic parameters, and the GH/IGF-1 axis in animal models of aging, GH deficiency, and metabolic syndrome. Its extended half-life makes it a valuable research tool for studies requiring prolonged GH axis stimulation without the confound of frequent injection stress in animal models.

Typical Research Parameters

In published human pharmacokinetic research, CJC-1295 with DAC was studied at single subcutaneous doses of 30–120 mcg/kg, producing dose-dependent GH area-under-the-curve responses. The compound is typically studied alongside a GHSR agonist (such as ipamorelin or GHRP-2) in combination paradigms to leverage the synergy between GHRH and ghrelin receptor systems. In animal model research, weekly subcutaneous dosing schedules have been employed, with serum IGF-1 and 24-hour GH pulse analysis as primary pharmacodynamic endpoints. Body composition (DXA, MRI), nitrogen balance, and tissue-specific gene expression endpoints are employed in longer-duration studies. For research use only.

Storage Requirements

CJC-1295 with DAC in lyophilized form should be stored at -20°C, protected from light and moisture. The maleimide-albumin conjugation chemistry used in the Drug Affinity Complex means that the free maleimide moiety on the unconjugated peptide (before administration) can undergo hydrolysis at neutral to basic pH, converting to a non-reactive maleamic acid form. This hydrolysis is a stability concern particularly in reconstituted solutions stored above pH 7. Reconstitution with slightly acidic sterile water (pH 4.5–6.5) and storage at 2–8°C with use within 14–21 days is recommended. Avoid alkaline conditions and extended storage of reconstituted solutions.

Safety Notes and Research Considerations

The extended half-life of CJC-1295 with DAC means that any adverse effects in animal models will be more prolonged than with short-acting GHRH analogues, a consideration relevant to study design and humane endpoint planning. Sustained elevation of GH and IGF-1 has implications for glucose homeostasis (GH-induced insulin resistance), cell proliferation endpoints (IGF-1 receptor signaling), and organ growth parameters in chronic dosing models. Antibody formation against the albumin-conjugated peptide has been evaluated in clinical research and warrants inclusion in immunological monitoring in animal studies involving repeated dosing. The interaction with endogenous albumin means that protein binding assays and pharmacokinetic studies employing standard free-fraction measurements will require adaptation. All research use must be conducted within appropriate institutional oversight frameworks. This compound is for research purposes only.