Variations of Modified GRF (1-29)

Not all modified GRF (1-29) is the same. In fact, falling under the umbrella of modified GRF (1-29) are at least four different molecular variations of the already modified protein. Knowing the differences between the various preparations of modified GRF (1-29) requires one to look at the amino acid sequence of the peptide in question.

 

GRF (1-29)

 

In its purest form, GRF (1-29) is simply the first 29 amino acids of naturally occurring human growth-hormone releasing hormone (hGHRH). This preparation is just as potent as hGHRH, acting to increase growth hormone production and release by binding to the growth hormone receptor cells found on the anterior pituitary gland.

 

Unfortunately, pure GRF (1-29) has a significantly reduced half-life compared to hGHRH. This is a function of increased metabolic degradation of GRF (1-29). As a result of this shortened half-life, scientists have altered the structure of GRF (1-29) in an effort to create a more potent, longer-lasting molecule.

 

Amino Acid Sequence of GRF (1-29):

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-NH2

 

Modified GRF (1-29)

 

An early attempt at modifying GRF (1-29) produced the molecule known as modified GRF (1-29) (a.k.a. mod GRF (1-29) or tetrasubstituted GRF (1-29)). This molecule is identical to GRF (1-29), with the exception of four amino acid substitutions. These substitutions act to prevent specific types of metabolic degradation and increase the potency of the molecule. The changes are bolded and underlined in the amino acid sequence below and the effect of each change is explained in the following list.

 

.   The alteration of Ala to D-Ala (position 2) prevents cleavage (breakage) of the bond between Ala and Asp by the enzyme dipeptidyl peptidase-4 (DDP-IV). Once cleaved, GRF (1-29) loses all biological activity.

.   The substitution of Gln for Asn (position 8) protects against amid hydrolysis as well as asparagine rearrangement. Both changes render GRF (1-29) inactive.

.   The substitution of Ala for Gly (position 15) enhances receptor binding, allowing modified GRF (1-29) to bind faster than GRF (1-29) and to stay bound for a longer duration. The result is increased release of growth hormone for the same amount of peptide.

.   The use of Leu in place of Met (position 27), prevents methionine oxidation from occurring1,2 . Oxidation of the sulfur atom on methionine changes the structure of GRF (1-29), preventing it from binding to the GHRH receptor.

 

Amino Acid Sequence of Modified GRF (1-29):

Tyr-D-AlaAsp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH2

 

 

CJC-1295 and CJC-1295-DAC

 

A great deal of confusion arises when discussing CJC-1295. Many people insist that CJC-1295 is modified GRF (1-29) and some insist that it is not. CJC-1295 is, technically, the same molecule as mod GRF (1-29). Originally, CJC-1295 was actually CJC-1295-DAC (discussed below), but nomenclature has been used quite loosely. Today, most products labeled CJC-1295 are identical to modified GRF (1-29). Unfortunately, the only way to be certain of what a product labeled CJC-1295 contains is to examine the amino acid sequence.

 

CJC-1295-DAC is modified GRF (1-29) to which an additional amino acid and a molecule called the drug affinity complex (DAC) are attached. CJC-1295-DAC has a much longer serum (blood) half-life because the DAC can bind to the naturally occurring protein albumin. When bound to albumin, CJC-1295-DAC is immune to normal metabolic degradation. The half-life increases from just 30 minutes to well over 8 hours3 .

 

Amino Acid Sequence of CJC-1295-DAC:

Tyr-D-AlaAsp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-Lys-DAC

 

CJC-1293

 

CJC-1293 is not like modified GRF (1-29) in most respects and is more like standard GRF (1-29). It does, however, contain the DAC molecule. The only differences between CJC-1293 and GRF (1-29) are the addition of DAC to CJC-1293 and the substitution of Ala for D-Ala at position 2. CJC-1293 has a shorter half-life than CJC-12953 .

 

Amino Acid Sequence of CJC-1293:

Tyr- D-AlaAsp-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-Lys-DAC

 

CJC-1288

 

CJC-1288 is simply GRF (1-29) to which the DAC complex has been added. Unlike CJC-1293 and CJC-1295, there are no amino acid substitutions in CJC-12883 .

 

Amino Acid Sequence of CJC-1288:

Tyr-AlaAsp-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-Lys-DAC

 

The Bottom Line

 

GRF (1-29) is the first 29 amino acids of naturally occurring human growth hormone releasing hormone. When DAC is added to the end of GRF (1-29), it becomes CJC-1288. When the second amino acid of CJC-1288 is modified from Ala to D-Ala, the molecule becomes CJC-1293. When the amino acids at positions 8, 15, and 27 of CJC-1293 are modified, it becomes CJC-1295-DAC. When DAC is removed from CJC-1295-DAC, it becomes CJC-1295 or modified GRF (1-29). The molecular structure of CJC-1295 should always be investigated to determine if it does or does not contain DAC because terminology is often used interchangeably.

 

Resources

 

  1. Frohman, L. A. et al. Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus. J. Clin. Invest.78, 906-913 (1986).

 

  1. Izdebski, J. et al. New potent hGH-RH analogues with increased resistance to enzymatic degradation. J. Pept. Sci. Off. Publ. Eur. Pept. Soc.8, 289-296 (2002).

 

  1. Jetté, L. 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. Endocrinology146, 3052-3058 (2005).

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