CJC-1295 Without DAC: A Research Overview

Introduction

CJC-1295 without DAC — also known in the scientific literature as Modified GRF 1-29, Mod GRF 1-29, or tetrasubstituted GRF(1-29) — is a synthetic 29-amino acid peptide analog of endogenous growth hormone-releasing hormone (GHRH). It belongs to the pharmacological class of growth hormone secretagogues (GHS) that act at the GHRH receptor on anterior pituitary somatotroph cells. The compound differs structurally and pharmacokinetically from CJC-1295 with DAC (Drug Affinity Complex), which incorporates an additional albumin-binding maleimidopropionyl moiety absent from the without-DAC variant. This article provides an educational reference overview of CJC-1295 without DAC based on published primary literature and regulatory documents.

Background

The foundational compound underlying CJC-1295 without DAC is human GRF(1-29)-NH2, commercially designated sermorelin — the biologically active N-terminal 29-amino acid fragment of native 44-amino acid GHRH. Research beginning in the early 1970s through the work of multiple groups established that the first 29 residues of GHRH retain full binding activity at the pituitary GHRH receptor, and that the C-terminal residues beyond position 29 are not required for receptor engagement [1].

Native hGRF(1-29) is cleared rapidly from plasma. The primary degradation pathway involves cleavage at the Tyr¹-Ala² N-terminal bond by the serine protease dipeptidyl peptidase-4 (DPP-4), generating the biologically inactive fragment GRF(3-29). Frohman and colleagues characterized these proteolytic pathways in detail, identifying DPP-4 cleavage as the dominant mechanism limiting the circulating half-life of native GHRH to roughly ten to twenty minutes in vivo [2]. This pharmacological finding catalyzed decades of analog design directed at conferring enzymatic resistance while preserving receptor-binding activity.

CJC-1295 without DAC represents the product of that design effort: a tetrasubstituted variant of hGRF(1-29) in which four specific residues are replaced to stabilize the molecule against proteolytic cleavage, extending its plasma persistence relative to the unmodified precursor.

Chemistry and Structure

CJC-1295 without DAC is a 29-amino acid synthetic peptide with a molecular formula reflecting four conservative amino acid substitutions relative to the native hGRF(1-29) sequence. The four substituted positions are:

• Position 2: L-Alanine replaced by D-Alanine (D-Ala²) — the primary modification conferring DPP-4 resistance at the N-terminal cleavage site
• Position 8: Asparagine replaced by Glutamine (Gln⁸) — stabilizes the peptide against secondary proteolysis
• Position 15: Glycine replaced by Alanine (Ala¹⁵) — contributes to overall conformational stability
• Position 27: Methionine replaced by Leucine (Nle²⁷) — eliminates an oxidation-susceptible residue, improving chemical stability

These substitutions are the same four modifications incorporated into CJC-1295 with DAC. What distinguishes CJC-1295 without DAC from its DAC-bearing counterpart is the absence of the C-terminal lysine-linked N-ε-3-maleimidopropionamide (MPA) derivative. The DAC moiety in CJC-1295 with DAC enables covalent in vivo conjugation to the free thiol on Cys34 of circulating serum albumin, extending the plasma half-life to approximately eight days. Without the DAC moiety, CJC-1295 without DAC retains substantially greater plasma stability than native hGRF(1-29) by virtue of its four substitutions, but does not undergo albumin conjugation. Its effective half-life in plasma is consequently measured in tens of minutes rather than days [3].

The compound is synthesized by solid-phase peptide synthesis and is characterized by its molecular weight (approximately 3,367 daltons as the free base), peptide sequence, and the presence of an amidated C-terminus (-NH₂).

Pharmacological Classification

CJC-1295 without DAC is classified as a growth hormone secretagogue acting via the GHRH receptor (GHRH-R) pathway. More specifically, it is a GHRH-R agonist — a compound that binds and activates the pituitary somatotroph GHRH receptor to stimulate endogenous GH secretion. This distinguishes it mechanistically from a second class of growth hormone secretagogues that act via the GH secretagogue receptor (GHS-R, the ghrelin receptor).

Ishida and colleagues (2020), in a review of growth hormone secretagogue pharmacology published in JCSM Rapid Communications, delineated the distinction between these two secretagogue classes, noting that GHRH-receptor agonists such as sermorelin and its analogs stimulate GH secretion by acting on the somatotroph's canonical cAMP-PKA signaling pathway, whereas GHS-R agonists (including ghrelin mimetics such as ipamorelin and GHRP-2) engage a structurally and functionally distinct receptor [4].

The pharmacokinetic consequence of the without-DAC structure is of particular scientific interest: the compound produces a transient elevation in GHRH-receptor stimulation that approximates a discrete physiological pulse, offering a pharmacological profile distinct from the sustained tonic GHRH-receptor stimulation produced by CJC-1295 with DAC. This distinction has informed research into pulsatile versus tonic GH secretagogue pharmacology. The reported molecular pharmacology underlying this receptor interaction is reviewed in detail in the CJC-1295 without DAC mechanism of action article. Research-grade CJC-1295 without DAC from SpartaLabs is third-party tested and supplied with a batch-specific Certificate of Analysis.

Regulatory Context

The scientific lineage of CJC-1295 without DAC includes a compound with prior FDA approval. Sermorelin acetate (hGRF(1-29)-NH2, the unmodified predecessor) received FDA approval under the brand name Geref in 1997 for the treatment of idiopathic growth hormone deficiency in children with growth failure and as a diagnostic agent for assessing pituitary GH reserve. The Geref commercial product was voluntarily discontinued in 2008 for economic reasons; the FDA's 2013 Federal Register notice confirmed this withdrawal was not for reasons of safety or effectiveness [5] — a regulatory record that affirms the established safety profile of the GRF(1-29) pharmacological scaffold.

CJC-1295 without DAC (Modified GRF 1-29) as a distinct compound has not received FDA approval for any therapeutic indication. In December 2024, the FDA convened the Pharmacy Compounding Advisory Committee (PCAC) to evaluate CJC-1295 and several related GHRH analogs as candidate bulk drug substances under Section 503A of the Federal Food, Drug, and Cosmetic Act, reflecting continued regulatory and scientific engagement with this compound class. The committee's evaluation and any resulting regulatory determination remained subject to ongoing agency review as of publication. This compound is sold by SpartaLabs for research use only and is not intended for human therapeutic use.

Discovery History

The scientific lineage of CJC-1295 without DAC traces through four decades of GHRH research. In 1982, two independent groups published the structural characterization of human GHRH: Guillemin and colleagues identified and synthesized a 44-amino acid growth hormone-releasing factor from a pancreatic tumor causing acromegaly [6], and Rivier and colleagues separately characterized an equivalent peptide from a second acromegalic patient's pancreatic islet tumor [7]. These landmark reports established the primary structure of GHRH and opened research into its pharmacological exploitation.

Subsequent work demonstrated that only the first 29 amino acids of GHRH were required for full biological activity, and sermorelin — the 29-amino acid N-terminal fragment — was developed as a shorter synthetic analog. Efforts to extend the plasma half-life of GRF(1-29) through strategic amino acid substitutions led to the tetrasubstituted GRF(1-29) series, of which CJC-1295 without DAC is a member. The ConjuChem Inc. research program extended this work further by adding the albumin-binding DAC moiety to create CJC-1295 with DAC — a compound formally characterized in preclinical work by Jetté and colleagues in 2005 [3]. CJC-1295 without DAC, representing the tetrasubstituted scaffold without the albumin-binding extension, has been studied comparatively in this scientific context.

References

1. Prakash A, Goa KL. Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency. BioDrugs. 1999;12(2):139-157. PMID: 18031173. DOI: 10.2165/00063030-199912020-00007

2. Frohman LA, Downs TR, Heimer EP, Felix AM. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma. J Clin Invest. 1989;83(5):1533-1540. PMID: 2651468. DOI: 10.1172/JCI114049. PMC: PMC303858

3. Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, et al. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005;146(7):3052-3058. PMID: 15817669. DOI: 10.1210/en.2004-1286

4. Ishida J, Saitoh M, Doehner W, von Haehling S, Anker SD, Springer J. Growth hormone secretagogues: history, mechanism of action, and clinical development. JCSM Rapid Commun. 2020;3(1):25-37. DOI: 10.1002/rco2.9

5. US Food and Drug Administration. Federal Register: Determination that GEREF (Sermorelin Acetate) Injection was not withdrawn from sale for reasons of safety or effectiveness. Fed Regist. 2013;78(43):14201. Available at: https://www.federalregister.gov/documents/2013/03/04/2013-04827/determination-that-geref-sermorelin-acetate-injection

6. Guillemin R, Brazeau P, Böhlen P, Esch F, Ling N, Wehrenberg WB. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218(4572):585-587. PMID: 6812220. DOI: 10.1126/science.6812220

7. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982;300(5892):276-278. PMID: 6292724. DOI: 10.1038/300276a0