CJC-1295 No DAC

CJC-1295 No DAC — also catalogued as Modified GRF (1-29) or tetrasubstituted GRF (1-29) — is a 29-residue synthetic analog of the N-terminal fragment of growth-hormone-releasing hormone (GHRH, also written GRF). The unmodified GRF(1-29) fragment was characterized in the early 1980s as retaining the growth-hormone-releasing activity of the full-length 44-residue hormone, and it became the scaffold for a large medicinal-chemistry literature. The no-DAC molecule carries four amino-acid substitutions on that scaffold (D-Ala2, Gln8, Ala15, Leu27). It shares this exact tetrasubstituted core with a longer-acting, albumin-binding variant; the two differ only in that the albumin-binding form adds a C-terminal group that the no-DAC form lacks. Because of that difference, the no-DAC molecule is rapidly cleared, while the albumin-binding variant is long-circulating.

Most of the rigorous chemistry behind this molecule concerns the GRF(1-29) scaffold and the degradation pathways the four substitutions are designed to counter. Frohman and colleagues (Frohman et al., 1989) characterized how dipeptidyl-peptidase-IV (DPP-IV) and trypsin-like enzymes cleave GHRH in plasma, and showed that a D-amino-acid at position 2 blocks the principal cleavage — the rationale for the D-Ala2 substitution. Work on chemical degradation (Friedman et al., 1991; Bongers et al., 1992) examined how the asparagine at position 8 deamidates and isomerizes in aqueous solution and how residue substitution stabilizes the peptide, while Stevenson and colleagues related the rate of that deamidation to the peptide's secondary structure. The Gln8 substitution follows from this line of work, and the Leu27 substitution removes an oxidation-prone methionine. Broader structure-activity studies on the scaffold (Lance et al., 1984; Campbell, Bongers & Felix, 1995; Izdebski et al., 1995; Cai, Schally et al., 2014) mapped how N-terminal substitutions and helicity influence receptor activity, providing the basis for the Ala15 substitution. These studies describe degradation routes and structure-activity relationships, not human outcomes.

GHRH and its analogues act on the GHRH receptor (GHRHR), a class B1 G-protein-coupled receptor expressed on anterior-pituitary somatotrophs that couples to the stimulatory G protein (Gs) and raises intracellular cAMP. The structural basis was resolved by cryo-electron microscopy: Zhou and colleagues (Zhou et al., 2020) reported the structure of the human GHRH receptor bound to GHRH and Gs (deposited as PDB 7CZ5), describing how the peptide's C-terminal helix is captured by the receptor's extracellular domain while its N-terminus inserts into the transmembrane core to open the intracellular face for G-protein coupling. This sits within the broader class B1 GPCR structural framework established by cryo-EM studies of related peptide receptors. A review of GHRH-receptor signaling mechanisms (Halmos et al., 2023) summarizes the Gs / adenylyl-cyclase / cAMP pathway in somatotrophs. This receptor-level pharmacology applies to the shared tetrasubstituted core.

Because dedicated peer-reviewed studies of the no-DAC molecule on its own are sparse, much of what is understood about its receptor behavior is inferred from work on the GRF(1-29) scaffold and on the albumin-binding DAC variant, which share the identical four-substitution core. An early study of albumin-binding GRF(1-29) bioconjugates (Jetté et al., 2005) evaluated their in-vitro resistance to DPP-IV and their activity in a growth-hormone-secretion assay in cultured rat anterior-pituitary cells, and characterized the exact tetrasubstituted core that constitutes the no-DAC compound. Porcine-model work (Dubreuil et al., 2001) characterized the receptor specificity of GRF analogues. Studies of the long-acting DAC variant examined the growth-hormone / IGF-1 axis in a GHRH-knockout mouse model (Alba et al., 2006), in serum-proteome profiling (Sackmann-Sala et al., 2009), and in clinical pharmacology studies of the GH / IGF-1 axis (Teichman et al., 2006; Ionescu & Frohman, 2006). A registered Phase 2 clinical study of the DAC variant is listed in the public trial registry (NCT00267527). All of these human and animal findings belong to the DAC variant or the scaffold, not to the no-DAC molecule specifically.

The literature draws a clear line that this catalog preserves: the no-DAC molecule and the DAC variant share an identical 29-residue, four-substitution GHRH(1-29) core, but only the DAC variant carries the C-terminal albumin-binding group that makes it long-circulating. Pharmacokinetic and human-study observations are properties of the DAC variant; the no-DAC molecule, lacking that group, is short-circulating and is best characterized at the level of the scaffold's receptor pharmacology and degradation chemistry rather than by the DAC variant's profile.