Peptide design using a genetically patterned binary code: growth hormone-releasing hormone as a model.
This paper reviews a method for the design of peptides and proteins of predefined structure and function and provides an example. Specifically, an analog of rat growth hormone-releasing hormone (GHRH) (residues 1-23) was synthesized by solid-phase methods based on a reversed sequence of the mRNA for GHRH (1-23). The new peptide, designated GHRH 3'-5', had a hydropathic profile similar to that of native GHRH 5'-3' (GHRH) but had only 17% primary sequence homology. GHRH 3'-5' specifically bound to the GHRH receptor on rat pituitary cells and to polyclonal anti-GHRH antibody in ELISA and RIA procedures. Additionally, GHRH 3'-5' blocked the in vitro stimulation of GH RNA synthesis and in vitro and in vivo GH release mediated by GHRH. These data show that 3'-5' GHRH with little sequence homology to native rat GHRH is an antagonist and further supports the importance of the linear pattern of hydropathy to the gross secondary and/or tertiary structure and rudimentary function of peptides and proteins. The impact of these findings on the interaction of complementary peptides is discussed.
Weigent
D A
DA
Department of Physiology and Biophysics, University of Alabama, Birmingham 35294-0005.
Clarke
B L
BL
Blalock
J E
JE
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D002478:Cells, Cultured; D018076:DNA, Complementary; D015195:Drug Design; D013006:Growth Hormone / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011506:Proteins / Q000737:chemistry*; D012333:RNA, Messenger / Q000032:analysis; D011863:Radioimmunoassay; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D011506:Proteins; D012333:RNA, Messenger; C092325:somatotropin-releasing hormone (1-23), 3'-5'; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone