Mod GRF 1-29
Also known as: Modified GRF (1-29), Tetrasubstituted GRF (1-29), CJC-1295 without DAC, Mod GRF(1-29), Modified growth hormone-releasing factor (1-29)
Mod GRF 1-29 is a tetrasubstituted analog of GRF(1-29), the shortest fully active fragment of growth hormone-releasing hormone, engineered for enzymatic stability; it is identical to the peptide core of CJC-1295 but lacks the Drug Affinity Complex (DAC) albumin-binding linker.
Key Findings at a Glance
- • Mod GRF 1-29 is the tetrasubstituted GRF(1-29) peptide core of CJC-1295 without the DAC albumin-binding linker; the two share a molecule but not a duration of action.
- • The D-Ala2 substitution cut metabolic clearance roughly in half in normal men (21 versus 39.7 mL/kg/min) and lengthened the disappearance half-time from 4.3 to 6.7 minutes.
- • No human trial has tested the no-DAC peptide alone; human GH and safety data attributed to it come from CJC-1295 studies of the same core in albumin-conjugated form.
- • Continuous GHRH receptor stimulation by this peptide core raises trough GH 7.5-fold while preserving the frequency and magnitude of natural GH pulses.
Mod GRF 1-29 Overview & Molecular Profile
Mod GRF 1-29 is a stabilized analog of GRF(1-29)NH2, the 29-amino-acid N-terminal fragment of growth hormone-releasing hormone that retains full receptor activity and is itself the active ingredient of sermorelin. The 'tetrasubstituted' designation refers to four amino acid changes that slow enzymatic degradation, the best characterized being D-Ala at position 2, which protects against dipeptidylpeptidase-IV cleavage. ConjuChem selected this exact peptide as the bioactive core of CJC-1295, in which a reactive linker conjugates it to serum albumin; Mod GRF 1-29 is the same core without that linker, so it circulates for minutes rather than days. Critically, no human clinical trial has evaluated the no-DAC peptide alone: the human safety and efficacy data commonly attributed to it come from CJC-1295 studies and from infusion studies of D-Ala2-substituted GRF(1-29).
Mechanism of Action: Hormonal Signaling & Receptor Binding
Mod GRF 1-29 is an agonist of the pituitary GHRH receptor (GHRHR), a Gs-coupled receptor on somatotroph cells whose activation raises intracellular cAMP and drives synthesis and pulsatile release of growth hormone. Like native GRF(1-29), it acts upstream of GH rather than replacing it, so its effect depends on an intact pituitary and preserves the body's own feedback control. The D-Ala2 substitution demonstrably improves pharmacokinetics: in normal men, the D-Ala2 analog showed a metabolic clearance rate of 21 +/- 1.2 mL/kg/min versus 39.7 +/- 3.9 for unmodified GRF(1-29)NH2, and a disappearance half-time of 6.7 versus 4.3 minutes. Studies of the long-acting conjugate CJC-1295 show that continuous GHRH receptor stimulation by this peptide core elevates trough GH levels 7.5-fold while preserving the frequency and magnitude of natural GH pulses, rather than flattening secretion into a non-physiological plateau.
Mod GRF 1-29 Pharmacokinetics: Minutes Without Albumin, Days With
This peptide's pharmacokinetics are defined by a subtraction. The tetrasubstituted GRF(1-29) core resists enzymatic cleavage but is still cleared in minutes; only the DAC linker of CJC-1295 turns the same core into a multi-day drug. Because no human trial has measured the no-DAC peptide directly, its profile is triangulated from infusion studies of the D-Ala2 analog and from CJC-1295 studies of the identical core.
The D-Ala2 Substitution Buys Minutes, Not Days
The signature modification of this analog class has a measured — and modest — pharmacokinetic effect in humans.
- • Halved Clearance: In 10 normal men infused intravenously with GRF(1-29)NH2 and its D-Ala2 analog (25 ng/kg/min), the analog's metabolic clearance rate was 21 +/- 1.2 versus 39.7 +/- 3.9 mL/kg/min (P<0.001), and its disappearance half-time was 6.7 +/- 0.5 versus 4.3 +/- 1.4 minutes (P<0.05) (PMID 7962295).
- • Mechanism Confirmed: The investigators concluded the D-Ala2 substitution enhances biological activity specifically by reducing metabolic clearance — protection against DPP-IV cleavage at the Ala2-Asp3 bond, not increased receptor potency (PMID 7962295).
- • The Practical Consequence: Even halved, clearance remains minutes-scale, which is why research protocols for the no-DAC peptide use multiple daily subcutaneous doses and why any once-weekly claim for this molecule is pharmacokinetically incoherent (PMID 7962295).
What the DAC Linker Adds
ConjuChem's conjugation program shows exactly what the missing linker does to the same peptide core.
- • Albumin Bioconjugation: Maleimidopropionyl derivatives of the tetrasubstituted hGRF(1-29) core covalently bind the Cys34 thiol of serum albumin after injection; the lead conjugate, CJC-1295, remained detectable in rat plasma beyond 72 hours and produced a 4-fold greater GH area under the curve than hGRF(1-29) (PMID 15817669).
- • Multi-Day Human Exposure: In healthy adults, single subcutaneous CJC-1295 doses produced GH increases of 2- to 10-fold lasting 6 or more days and IGF-1 increases of 1.5- to 3-fold lasting 9-11 days, with an estimated half-life of 5.8-8.1 days; IGF-1 remained above baseline for up to 28 days after multiple doses (PMID 16352683).
- • Two Molecules, One Name: The unconjugated core produced only acute GH release in the same rat program that showed the conjugate riding on circulating albumin — the entire duration difference resides in the linker, not the peptide (PMID 15817669).
Pulsatile Versus Sustained Elevation
The two forms of this peptide core produce fundamentally different growth hormone secretory patterns.
- • Preserved Pulsatility Under Continuous Stimulation: Overnight 20-minute sampling in healthy men one week after a single CJC-1295 injection (60 or 90 µg/kg) showed GH pulse frequency and magnitude unchanged while basal trough GH rose 7.5-fold (P<0.0001), mean GH rose 46%, and IGF-1 rose 45% — continuous receptor stimulation lifts the baseline without flattening pulses (PMID 17018654).
- • The No-DAC Alternative: Brief, minutes-scale exposure from the unlinked core produces discrete GHRH receptor stimulation episodes that track the timing of endogenous GHRH spikes, in contrast to the week-long trough elevation of the conjugated form (PMID 7962295).
- • Why the Distinction Matters: GH-axis physiology and feedback differ between pulsatile and sustained stimulation, so data generated on CJC-1295 cannot be assumed to transfer to the no-DAC peptide — the pharmacokinetic gap between them is the difference between two dosing paradigms (PMID 16352683).
Research-Observed Effects
Pulsatile GH Release with Preserved Physiology
Moderate ResearchWork by Ionescu and Frohman (JCEM 2006) on the albumin-conjugated form of this peptide core showed that even continuous GHRH receptor stimulation leaves the architecture of GH secretion intact: after a single injection, GH secretory pulse frequency and magnitude were unaltered, while basal trough GH rose 7.5-fold (P<0.0001), mean GH rose 46%, and IGF-1 rose 45%. This supports the central pharmacological claim for GHRH analogs over exogenous GH: they amplify the body's own pulsatile rhythm instead of overriding it, preserving somatostatin-mediated feedback.
Resistance to Enzymatic Degradation
Moderate ResearchNative GRF(1-29) is cleared within minutes, largely through DPP-IV cleavage at the Ala2-Asp3 bond. The D-Ala2 substitution shared by this analog class was shown in normal men to cut metabolic clearance roughly in half (21 +/- 1.2 versus 39.7 +/- 3.9 mL/kg/min; P<0.001) and to extend the disappearance half-time from 4.3 to 6.7 minutes (P<0.05), directly linking the substitution to enhanced biological activity. ConjuChem's conjugation program confirmed that the tetrasubstituted core retained full GRF receptor activation on rat anterior pituitary cells with enhanced stability against dipeptidylpeptidase-IV.
Sustained GH and IGF-1 Elevation as the CJC-1295 Core
Moderate ResearchWhen this same tetrasubstituted peptide is conjugated to albumin as CJC-1295, single subcutaneous doses in healthy adults produced dose-dependent GH increases of 2- to 10-fold lasting 6 days or more and IGF-1 increases of 1.5- to 3-fold lasting 9-11 days, with an estimated half-life of 5.8-8.1 days and no serious adverse reactions at 30-60 µg/kg. These data describe the core's intrinsic potency at the GHRH receptor; they do not transfer to the no-DAC peptide's minutes-scale exposure, which is why the DAC version was developed in the first place.
Short Half-Life Without the DAC Linker
Preliminary ResearchThe defining practical feature of Mod GRF 1-29 is what it lacks: without the maleimidopropionyl linker that binds albumin's Cys34 thiol, the peptide cannot bioconjugate and is cleared in minutes. Rat studies in the ConjuChem program showed the unconjugated hGRF(1-29) analog produced only acute GH release, while the conjugated CJC-1295 remained detectable in plasma beyond 72 hours. Research protocols therefore use multiple daily subcutaneous doses, and any claim of week-long activity for 'CJC-1295 without DAC' conflates two pharmacokinetically distinct molecules.
Research Protocol Doses Reported in Published Literature
Research Disclaimer: Doses reported below are from published preclinical research protocols. Mod GRF 1-29 is not approved for human use by the FDA or any regulatory agency. This information is provided for research reference only and does not constitute a dosing recommendation.
| Route | Dose | Frequency | Notes |
|---|---|---|---|
| Subcutaneous (research only) | Not established in humans | Multiple times daily (minutes-scale half-life without DAC) | No standalone human trials; human safety data come from CJC-1295 (same core + DAC), where 30–60 µg/kg was well tolerated |
All doses above are reported from published research protocols using laboratory subjects. Refer to the cited studies in the Research Studies section above for original source data.
Research Studies & References
Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men
Soule S, King JA, Millar RP
Journal of Clinical Endocrinology and Metabolism (1994)
This study infused GRF(1-29)NH2 and its D-Ala2-substituted analog intravenously (25 ng/kg/min) in 10 normal men and measured analog levels during and after infusion. The D-Ala2 analog had a significantly lower metabolic clearance rate (21 +/- 1.2 versus 39.7 +/- 3.9 mL/kg/min; P<0.001) and a longer disappearance half-time (6.7 +/- 0.5 versus 4.3 +/- 1.4 minutes; P<0.05). The authors concluded that the D-Ala2 substitution, a hallmark of the modified GRF(1-29) class, enhances biological activity specifically by reducing metabolic clearance.
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
Jetté L, Léger R, Thibaudeau K, et al.
Endocrinology (2005)
The ConjuChem team synthesized maleimido derivatives of tetrasubstituted hGRF(1-29) designed to bioconjugate to the Cys34 thiol of serum albumin after injection. All conjugates showed enhanced stability against dipeptidylpeptidase-IV and activated the GRF receptor in cultured rat anterior pituitary cells. The lead compound, CJC-1295, produced a 4-fold increase in GH area under the curve over 2 hours versus hGRF(1-29) in rats and remained in plasma beyond 72 hours, with Western blotting confirming the peptide riding on circulating albumin. This paper defines the tetrasubstituted GRF(1-29) core that Mod GRF 1-29 comprises without the reactive linker.
Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults
Teichman SL, Neale A, Lawrence B, et al.
Journal of Clinical Endocrinology and Metabolism (2006)
Two randomized, double-blind, placebo-controlled ascending-dose trials in healthy adults aged 21-61 characterized CJC-1295, the albumin-conjugated form of the Mod GRF 1-29 core. Single subcutaneous doses produced dose-dependent mean GH increases of 2- to 10-fold for 6 days or more and IGF-1 increases of 1.5- to 3-fold for 9-11 days, with an estimated half-life of 5.8-8.1 days; after multiple doses, IGF-1 remained above baseline for up to 28 days. No serious adverse reactions occurred, with best tolerability at 30 or 60 µg/kg, establishing the human pharmacology of this peptide core in its long-acting form.
Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog
Ionescu M, Frohman LA
Journal of Clinical Endocrinology and Metabolism (2006)
Ionescu and Frohman performed 20-minute overnight blood sampling in healthy men aged 20-40 before and 1 week after a single CJC-1295 injection (60 or 90 µg/kg). Continuous GHRH receptor stimulation preserved GH pulsatility: pulse frequency and magnitude were unaltered, while basal trough GH rose 7.5-fold (P<0.0001), mean GH rose 46% (P<0.01), and IGF-1 rose 45% (P<0.001). The study demonstrates that this GRF(1-29)-derived core amplifies endogenous GH secretion by raising the baseline between pulses rather than abolishing the pulsatile pattern.
Comparative Research
Explore in-depth research analyses and comparative studies featuring Mod GRF 1-29.
Frequently Asked Questions
What is the difference between Mod GRF 1-29 and CJC-1295?
They share the identical bioactive peptide: a tetrasubstituted analog of GRF(1-29). CJC-1295 adds the Drug Affinity Complex (DAC), a maleimidopropionyl group on a C-terminal lysine that covalently binds the Cys34 residue of serum albumin after injection. That single modification changes the pharmacokinetics from minutes to 5.8-8.1 days of circulation. Mod GRF 1-29, sold in research markets as 'CJC-1295 without DAC', is the same core peptide without the linker, so it requires multiple daily doses and produces brief, pulsatile stimulation rather than week-long elevation.
Has Mod GRF 1-29 itself been tested in humans?
No. There is no published human clinical trial of the no-DAC tetrasubstituted GRF(1-29) peptide as a standalone drug. The human data attached to this molecule come from two adjacent bodies of work: CJC-1295 trials (Teichman 2006; Ionescu and Frohman 2006), which used the same peptide core conjugated to albumin, and infusion studies of the singly substituted D-Ala2-GRF(1-29) analog (Soule 1994), which demonstrated the pharmacokinetic benefit of the position-2 substitution. Any dosing guidance circulating online extrapolates beyond the published evidence.
Why is it called 'tetrasubstituted'?
The peptide carries four amino acid substitutions relative to native GRF(1-29), introduced to resist enzymatic degradation and improve stability. The ConjuChem identification paper (Jetté 2005) describes CJC-1295 explicitly as a tetrasubstituted form of hGRF(1-29) with an added C-terminal lysine derivative. The best-documented single change is D-Ala at position 2, which blocks DPP-IV cleavage and was independently shown in normal men to roughly halve metabolic clearance compared with unmodified GRF(1-29)NH2.
How does Mod GRF 1-29 differ from sermorelin?
Sermorelin is unmodified GRF(1-29)NH2, the native 29-amino-acid GHRH fragment; it was FDA-approved as Geref for diagnostic and pediatric use before being withdrawn in 2009 for commercial, non-safety reasons. Mod GRF 1-29 is the same 29-residue scaffold carrying four stabilizing substitutions. Both are short-lived in circulation (sermorelin's half-life is also minutes-scale), and both require an intact pituitary to work. Tesamorelin, the one GHRH-class drug currently FDA-approved, is a different, longer 44-residue analog with a lipophilic modification.
Why does the DAC linker matter so much?
The DAC is the entire reason CJC-1295 exists. Jetté and colleagues showed that attaching a maleimidopropionyl group to the peptide lets it covalently bioconjugate to albumin within minutes of injection, creating a circulating drug reservoir detectable beyond 72 hours and a 4-fold greater GH response in rats. Without it, the peptide core is cleared almost immediately. Claims that 'CJC-1295 without DAC' provides the same long action are a contradiction: removing the DAC removes the long action that defines CJC-1295.
Does continuous GHRH stimulation flatten natural GH pulses?
Evidence says no. In the Ionescu and Frohman sampling study, a week of continuous receptor stimulation by the long-acting form of this peptide left GH pulse frequency and pulse magnitude unchanged while raising the trough between pulses 7.5-fold and mean GH by 46%. GHRH analogs therefore amplify the body's existing pulsatile rhythm, in contrast to injections of recombinant GH, which impose an exogenous, non-pulsatile level and shut down endogenous secretion through negative feedback.
What does the D-Ala2 substitution actually do?
Native GRF(1-29) is rapidly inactivated when the enzyme DPP-IV cleaves it at the Ala2-Asp3 bond. Replacing L-alanine with its D-isomer at position 2 makes the peptide a poor substrate for the enzyme. In a controlled infusion study in 10 normal men, the D-Ala2 analog's metabolic clearance fell from 39.7 to 21 mL/kg/min and its disappearance half-time lengthened from 4.3 to 6.7 minutes. The effect is real but modest in absolute terms, which is why further engineering, including the DAC approach, was pursued.
Is Mod GRF 1-29 approved or legally sold?
No. Mod GRF 1-29 has no approved medical use in any jurisdiction and is sold only as a research chemical, with the purity and identity risks that entails. Within the GHRH class, tesamorelin (Egrifta) is the FDA-approved drug, sermorelin was formerly approved and later withdrawn, and CJC-1295, like its no-DAC core, remains investigational. Products marketed online under this name are not the clinically studied molecule and carry no quality guarantee.
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