RATIONAL DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NOVEL GROWTH-HORMONE RELEASING-FACTOR ANALOGS

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. Substantia l research has been focused upon the development of potent, long-actin g analogs as therapeutics. Herein is described a summary of the cumula tive efforts of various laboratories endeavoring in this guest. The ra tionale utilized in GRF analog development is discussed. I) determinat ion of bioactive core 2) evaluation of secondary structure, and 3) elu cidation of degradation pathways (chemical and enzymatic. Using this i nformation, several series of linear (unnatural and natural sequence) and cyclic GRF analogs were designed, synthesized, and evaluated. Stim ulated by the constraints of commercial production, innovative, altern ative methods of synthesis were explored: solid-phase, solution-phase, enzymatic, and recombinant. To date, the most promising candidate for drug development is [His(1), Val(2), Gln(8), Ala(15), Leu(27)]-hGRF(1 -32)-OH. This natural sequence analog, consisting of rodent and human sequences, incorporates the bioactive core, preferred secondary struct ure, resistance to chemical and enzymatic degradation; with the added benefit of amenability to large-scale recombinant synthesis. (C) 1995 John Wiley & Sons, Inc.