GH-RH analogs with potent agonistic effects
Inventors
Schally, Andrew V • Cai, Ren Zhi • Zarandi, Marta
Assignees
University of Miami • US Department of Veterans Affairs
Publication Number
US-9079974-B2
Publication Date
2015-07-14
Expiration Date
2031-12-21
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Abstract
There are provided a novel series of peptide analogs of hGH-RH(1-29)NH2 and hGH-RH(1-30)NH2 which show high activities in stimulating the release of pituitary GH in animals. They retain their physiological activity in solution for extended periods of time and resist enzymic degradation in the body. These novel and useful properties appear to be due to novel substitution patterns ant at the 1, 15, 27 and 29 positions on the peptide.
Core Innovation
The invention relates to novel synthetic peptide analogs of human growth hormone-releasing hormone (hGH-RH) comprising 29 or 30 amino acids that exhibit high activities in stimulating the release of pituitary growth hormone (GH) in animals, including humans. These analogs have extremely high binding capacity to the hGH-RH receptor and demonstrate prolonged retention of physiological activity in solution, combined with resistance to enzymatic degradation in vivo. The potent GH-releasing properties of these new analogs result from multiple specific amino acid substitutions at positions 1, 8, 12, 15, 20, 21, 27, 28, 29, and optionally 30, and from modifications at the N- and C- termini that confer enhanced stability and biological activity compared to native hGH-RH(1-29)NH2.
The problem addressed by the invention arises from the rapid enzymatic and chemical degradation of native hGH-RH and its known analogs in plasma and tissues, which limits their biological potency and clinical utility. Specifically, native hGH-RH is rapidly inactivated by enzymes such as dipeptidylpeptidase IV, chymotrypsin-like enzymes, and trypsin-like enzymes at specific cleavage sites, as well as by chemical processes that reduce bioactivity. This instability necessitates the development of long-acting GH-RH analogs with substitutions that prevent enzymatic degradation at the N-terminus and C-terminus and improve resistance to oxidation and isomerization. Prior art analogs did not adequately address these stability issues or did not show improved affinity or potency in humans.
The present invention provides a detailed formula for these synthetic peptides, with specific possible substitutions at defined amino acid positions including N-methyl-tyrosine or des-amino-tyrosine at position 1; D-alanine or D-abutyrate at position 2; pentafluorophenylalanine at position 6; glutamine, alanine, threonine, or N-methyl-alanine at position 8; ornithine or lysine derivatives at positions 12 and 21; alpha-aminobutyric acid or alanine at position 15; norleucine at position 27; serine or aspartate at position 28; and arginine, agmatine, or related groups at positions 29 and 30 with various possible C-terminal modifications. These multiple substitutions provide enhanced receptor binding affinity, increased potency in vivo, improved enzymatic resistance, and prolonged activity relative to both native hormone and previously described analogs.
Claims Coverage
The patent includes a set of independent claims directed to specific synthetic peptide analogs of hGH-RH with defined substitution patterns and pharmaceutical compositions containing these peptides. The claims cover chemical structure formulas with particular amino acid substitutions and terminal modifications.
Peptide analog formula with specified amino acid substitutions and terminal modifications
The peptide analogs have a defined formula [R1-A1,A2,A6,A8,A11,A12,A15,A20,A21,A22,Nle27,A28,A29,A30]hGH-RH(1-30)-R2 where R1 is Ac, Tfa, or absent; specific amino acid substitutions occur at defined positions including Tyr, Dat, or N-Me-Tyr at A1; D-Ala or D-Abu at A2; Phe or Fpa5 at A6; Asn, Ala, Gln, Thr, or N-Me-Ala at A8; Arg, His, or Har at A11; Orn or Lys(Me)2 at A12; His, Abu, Aib, Aah, Aap, Ala, or D-Ala at A15; Arg, His, or Har at A20; Orn or Lys(Me)2 at A21; Leu or Orn at A22; Ser or Asp at A28; Arg, Har, Agm, D-Arg, or D-Har at A29; and various residues or absence at A30, with R2 as an alkylated amide, and pharmaceutically acceptable salts thereof.
Peptide analogs with preferred substitution pattern for enhanced activity
Analogs where A12 is ornithine, A15 is Abu, A20 is Arg, A21 is ornithine, A22 is Leu, A29 is Arg, D-Arg, or Agm, with additional specified amino acid substitutions at A1, A8, A11, and A30, representing preferred embodiments enhancing receptor binding and in vivo potency.
Pharmaceutical compositions containing the described GH-RH peptide analogs
Pharmaceutical formulations comprising therapeutically effective amounts of the claimed GH-RH peptide analogs with their defined amino acid substitutions and terminal modifications, along with pharmaceutically acceptable excipients.
The claims cover novel hGH-RH peptide analogs featuring multiple specific amino acid substitutions and C- and N-terminal modifications that provide enhanced receptor binding, increased resistance to enzymatic degradation, and greater in vivo GH-releasing potency, as well as pharmaceutical compositions containing these analogs.
Stated Advantages
Peptide analogs exhibit high binding affinity to the human GH-RH receptor and increased potency in stimulating GH release in vivo compared to native hGH-RH(1-29)NH2.
The analogs retain physiological activity in solution for extended periods and resist enzymatic degradation in the body, leading to longer duration of action.
In vivo tests demonstrated longer-lasting and stronger GH release after intravenous and subcutaneous administration relative to prior GH-RH peptides.
Certain salts of these analog peptides (e.g., pamoate salts) exhibit low solubility and provide a long duration of activity useful for sustained delivery.
Documented Applications
Treatment or prevention of growth hormone deficiency in humans and animals by promoting endogenous GH release.
Treatment of short stature in children due to GH deficiency or hypothalamic deficiencies, including conditions such as Turner's syndrome, familial short stature, and growth delay.
Use in geriatric patients to reduce loss of muscle, bone, and skin mass, lessening the increase of body fat associated with aging.
Applications in catabolic states, wound healing, delayed fracture healing, osteoporosis, obesity, cardiac failure, and as adjunct therapy in malnourished patients.
Promotion of growth and enhancement of milk production in lactating mammals such as cows and goats.
Diagnostic use to ascertain endogenous physiological capacity to produce human growth hormone by comparing GH responses to native GH-RH and the peptide analog.
Use during and after space flights to counteract decreased GH secretion due to weightlessness.
Administration via various routes including subcutaneous, intramuscular, intravenous, intranasal, pulmonary inhalation, or depot formulations such as microcapsules or implants.
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