CJC-1295 without DAC: Molecular Structure

Molecular Structure#

CJC-1295 without DAC, also known as Modified GRF(1-29), is a synthetic linear peptide consisting of 29 amino acid residues with a molecular weight of approximately 3,367.9 Da. The peptide is derived from the biologically active N-terminal fragment of human growth hormone-releasing hormone (GHRH, also known as growth hormone-releasing factor or GRF), which comprises residues 1-44 of the full GHRH sequence. The first 29 residues (GRF 1-29) represent the minimum sequence required for full agonist activity at the GHRH receptor.

The molecular formula is C152H252N44O42. The peptide is C-terminally amidated (CONH2 rather than COOH), which is consistent with the natural processing of GHRH and contributes to improved metabolic stability by preventing carboxypeptidase degradation.

Amino Acid Sequence and Modifications#

The native human GRF(1-29) sequence is: Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg.

The Modified GRF(1-29) sequence incorporates four strategic amino acid substitutions:

Position 2: Ala to D-Ala. This is the most critical modification. Native GHRH is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), which cleaves the Tyr1-Ala2 peptide bond. The D-Ala substitution introduces a non-natural amino acid configuration that DPP-IV cannot recognize, rendering the peptide resistant to this primary degradation pathway. This single modification extends the biological half-life from less than 7 minutes (native GHRH) to approximately 30 minutes.

Position 8: Asn to Gln. Asparagine at position 8 in native GHRH is susceptible to non-enzymatic deamidation to aspartate, a chemical degradation process that reduces potency and complicates formulation stability. The substitution of glutamine, which is structurally similar but resistant to deamidation under normal storage conditions, preserves receptor binding while improving shelf stability.

Position 15: Gly to Ala. This substitution enhances the overall metabolic stability of the peptide by reducing susceptibility to other endopeptidases. Glycine, as the smallest amino acid, provides less steric protection than alanine against protease cleavage at nearby bonds.

Position 27: Met to Leu. Methionine is susceptible to oxidation of its sulfur atom, forming methionine sulfoxide, which can reduce biological activity and complicates quality control. Leucine is sterically similar to methionine but lacks the oxidizable sulfur, providing improved chemical stability without affecting receptor interaction.

Structure-Activity Relationships#

The GHRH receptor binding pharmacophore resides primarily within the N-terminal region of the peptide, particularly residues 1 through 10. Structure-activity relationship studies have demonstrated that the N-terminal tyrosine (position 1) is essential for receptor activation. Residues 6 (Phe), 7 (Thr), 10 (Tyr), and 14 (Leu) are also critical for maintaining full agonist activity.

The C-terminal region (approximately residues 20 to 29) contributes to receptor affinity through alpha-helical stabilization but is less critical for intrinsic activity. This is why GRF(1-29) retains full agonist potency despite lacking residues 30 to 44 of the complete GHRH sequence. The amphipathic alpha-helical structure of the peptide, with hydrophobic residues on one face and hydrophilic residues on the other, is important for both receptor binding and membrane interaction.

Pharmacokinetic Properties#

Without the Drug Affinity Complex, Modified GRF(1-29) exhibits typical small peptide pharmacokinetics. After subcutaneous injection, the peptide is absorbed into the systemic circulation with a time to peak plasma concentration (Tmax) of approximately 5 to 15 minutes. The plasma half-life is approximately 30 minutes, reflecting proteolytic degradation and renal clearance.

The pharmacodynamic profile shows a GH pulse beginning within 5 to 10 minutes of subcutaneous injection, peaking at approximately 15 to 30 minutes, and returning to baseline within 1 to 2 hours. This discrete, time-limited GH pulse is in contrast to the sustained GH elevation produced by CJC-1295 DAC.

The bioavailability of subcutaneous Modified GRF(1-29) has not been precisely determined in published studies, but based on the general pharmacokinetics of similar-sized peptides, it is estimated at approximately 80 to 90%, reflecting the relatively efficient absorption of small peptides from subcutaneous tissue.

Chemical Properties and Stability#

Modified GRF(1-29) is supplied as a lyophilized white to off-white powder. The peptide is soluble in sterile water, bacteriostatic water, and physiological saline. The isoelectric point is approximately 10.2, reflecting the preponderance of basic residues (Arg, Lys).

The lyophilized form is stable for extended periods when stored at -20 degrees Celsius, protected from moisture and light. The reconstituted solution should be stored refrigerated at 2 to 8 degrees Celsius and used within 2 to 3 weeks. The four amino acid modifications substantially improve both enzymatic and chemical stability compared to native GRF(1-29), making Modified GRF(1-29) a more practical compound for research use.

Comparison with Native GRF(1-29) (Sermorelin)#

The key structural difference between Modified GRF(1-29) and sermorelin (native GRF 1-29) is the four amino acid substitutions described above. These modifications do not significantly alter the three-dimensional structure or receptor binding mode of the peptide but dramatically improve its metabolic stability.

Native GRF(1-29) has a plasma half-life of less than 7 to 10 minutes due to rapid DPP-IV cleavage, while Modified GRF(1-29) achieves approximately 30 minutes. Both peptides have identical GHRH receptor binding affinity and intrinsic agonist activity. The practical consequence is that Modified GRF(1-29) produces a more robust and sustained GH pulse per injection than sermorelin, as the peptide persists in the circulation long enough for more complete receptor engagement.

Related Reading#

• CJC-1295 without DAC overview and research guide
• Peptides similar to CJC-1295 without DAC
• CJC-1295 without DAC research evidence