Research Brief
CJC-1295: Mechanism of Action
1. DAC Technology — Albumin-Binding Mechanism
The DAC linker on CJC-1295 e um(a) N-ε-3-maleimidopropionyl (MPA) group attached para o(a) ε-amine of Lys29 no(a) C-terminus. After subcutaneo(a) injection, the maleimide group undergoes a thio-Michael addition com o(a) free thiol of serum albumin Cys-34 (the apenas free cysteine in circulating albumin), forming a stable, irreversible thioether bond. [1]
| Phase | Mecanismo | Result |
|---|---|---|
| 1. In vivo binding | MPA maleimide + albumin Cys-34 → thioether bond | CJC-1295 becomes albumin-conjugated; plasma t½ → 6–8 days |
| 2. Slow release | Albumin-CJC-1295 complex circulates; GHRHr remains accessible | Sustained GHRH receptor estimulacao for 9–11 days |
| 3. GHRHr ativacao | GHRHr → Gs → adenylyl cyclase → cAMP ↑ | PKA ativacao → GH gene transcricao in somatotrophs |
| 4. GH secretion | GH liberado(a) de anterior pituitary → circulation | GH → liver IGF-1 production; periferico(a) anabolic effects |
2. GHRHr Signaling Cascade
CJC-1295 engages the GHRH receptor (GHRHr), a class B G protein-coupled receptor expresso(a) em anterior pituitary somatotroph cells: [2]
- Gs/cAMP pathway: GHRHr → Gs → adenylyl cyclase → cAMP ↑ → PKA ativacao → fosforilacao of CREB → GH gene transcricao
- IP3/Ca²⁺ pathway: Secondary Gq coupling → PLC → IP3 → intracellular Ca²⁺ mobilization → GH vesicle exocytosis
- IGF-1 loop: GH → liver → IGF-1 production → periferico(a) tissues (muscle, bone, adipose) → anabolic signaling
- Negative feedback: Rising IGF-1 and somatostatin suppress further GH release — preserving physiological regulacao
3. CJC-1295 with DAC vs. No-DAC vs. Native GHRH
| Property | Native GHRH(1-44) | No-DAC (Mod GRF 1-29) | CJC-1295 with DAC |
|---|---|---|---|
| Half-life | ~7 min | ~30 min | 6–8 days |
| GH pattern | Pulsatile | Pulsatile | Tonic/continuous |
| Clinical trials | Yes (approved) | None (FDA Dec 2024) | Phase I/II (Teichman 2006) |
| IGF-1 elevation duration | Minutes | Hours | 9–11 days |
| Albumin binding | No | No | Yes (irreversible) |
4. DNA Damage Considerations
Preclinical research (Ben-Shlomo et al., 2020) has raised the hypothesis que sustained, continuous GH estimulacao via long-acting GHRH analogues may promote DNA damage in pituitary somatotroph cells — um(a) potenteial concern with tonic GH elevation diferentemente de the physiological pulsatile pattern. [6] This remains an ativo(a) area of mechanistic research e e ainda nao estabeleceu como um(a) clinical safety signal from human trial data.
Referencias
- Jetté L, et al. (2005). Human hormonio do crescimento-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor no(a) anterior pituitary in rats: identification of CJC-1295 como um(a) long-lasting GRF analog. Endocrinology, 146(7):3052–3058.
- Ionescu M, Frohman LA. (2006). Pulsatile secretion of hormonio do crescimento (GH) persists during continuous estimulacao by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab, 91(12):4792–4797.
- Teichman SL, et al. (2006). Prolonged estimulacao of hormonio do crescimento (GH) and insulin-like fator de crescimento I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in adultos saudaveis. J Clin Endocrinol Metab, 91(3):799–805.
- Alba M, et al. (2006). Once-monthly administration of CJC-1295, a long-acting hormonio do crescimento-releasing hormone (GHRH) analog, normalizes growth no(a) GHRH-deficient dwarf rat. Am J Physiol Endocrinol Metab, 291(6):E1290–E1294.
- Walker RF. (2006). Sermorelin: a better approach to management of adult-onset hormonio do crescimento insufficiency? Clin Interv Aging, 1(4):307–308.
- Ben-Shlomo A, et al. (2020). Growth hormone-releasing hormone (GHRH) e seu(sua) analogues: from bench to bedside. Neuroendocrinology, 110(3–4):192–199.
- Gahete MD, et al. (2009). In vivo e em vitro evidence para o(a) importance of hormonio do crescimento-releasing hormone no(a) regulacao of GH secretion. Mol Cell Endocrinol, 309(1–2):40–47.
- FDA. (2024). Substancia Farmaceutica a Granels Under Evaluation for Use in Compounding Under Section 503A: Categoria 2. Docket FDA-2013-N-1525. Federal Register, Dec 2024.
- WADA. (2024). List of Prohibited Substances and Methods. S2: Hormonios Peptidicos, Fatores de Crescimento, Substancias Relacionadas e Mimeticos. World Anti-Doping Agency.
- Frohman LA, Jansson JO. (1986). Growth hormone-releasing hormone. Endocr Rev, 7(3):223–253.
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