Rational design, synthesis, and biological evaluation of novel growth hormone releasing factor analogues.
Since its initial discovery in 1982, growth hormone-releasing factor (GRF) has been the subject of intense investigation. This interest was prompted by the potential application of GRF for stimulating growth in dwarf humans and for performance enhancement in livestock. Substantial research has been focused upon the development of potent, long-acting analogs as therapeutics. Herein is described a summary of the cumulative efforts of various laboratories endeavoring in this quest. The rationale utilized in GRF analog development is discussed: 1) determination of bioactive core, 2) evaluation of secondary structure, and 3) elucidation of degradation pathways (chemical and enzymatic). Using this information, several series of linear (unnatural and natural sequence) and cyclic GRF analogs were designed, synthesized, and evaluated. Stimulated by the constraints of commercial production, innovative, alternative methods of synthesis were explored: solid-phase, solution-phase, enzymatic, and recombinant. To date, the most promising candidate for drug development is [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-OH. This natural sequence analog, consisting of rodent and human sequences, incorporates the bioactive core, preferred secondary structure, resistance to chemical and enzymatic degradation; with the added benefit of amenability to large-scale recombinant synthesis.
Campbell
R M
RM
Hoffmann-La Roche, Inc., Roche Research Center, Nutley, New Jersey 07110.
Bongers
J
J
Felix
A M
AM
D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D004392:Dwarfism / Q000188:drug therapy; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D013007:Growth Hormone-Releasing Hormone