Introduction of a chemical constraint in a short peptide derived from human acidic fibroblast growth factor elicits mitogenic structural determinants.
Fibroblast growth factors (FGFs) are regulatory proteins associated with a number of physiological and pathological states. On the basis of data suggesting a functional role for specific regions of human acidic FGF (aFGF), a linear peptide encompassing residues 99-108 (peptide1) and its cyclic analogue (peptide 2) were synthesized and their functional and structural features were investigated. While peptide 1 is inactive on Balb/c 3T3 fibroblasts, peptide 2 is mitogenic with ED(50) of approximately 50 microM. Moreover, peptide 1 is not able to inhibit the binding of human aFGF to cellular receptors whereas peptide 2 exhibits significant inhibitory activity. The NMR-derived solution conformers indicated the presence, only in peptide 2, of structural elements that we believe are related to its ability to emulate the biological activity of the native protein. These results suggest that the expression of mitogenic activity in short peptides, besides the presence of specific amino acids, requires the existence of stable structural features. In addition, they indicate that the introduction of chemical restraints in peptides can provide novel possibilities for the development of receptor agonists or antagonists.
Kiyota
Sumika
S
Department of Biochemistry, Institute of Chemistry, University of São Paulo, P.O. Box 26077, Brazil.
Franzoni
Lorella
L
Nicastro
Giuseppe
G
Benedetti
Arianna
A
Oyama
Sérgio
S
Viviani
Wládia
W
Gambarini
Angelo G
AG
Spisni
Alberto
A
Miranda
M Terêsa M
MT
D016475:3T3 Cells; D000818:Animals; D002942:Circular Dichroism; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry*; D005346:Fibroblast Growth Factors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008934:Mitogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013936:Thymidine / Q000378:metabolism
D008934:Mitogens; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C475426:cysteinyl-lysyl-lysyl-histidyl-cysteinyl-glutamyl-lysyl-asparagyl-tryptophyl-phenylalaninamide (1-5)-disulfide; C475425:human acidic fibroblast growth factor (99-108) amide; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors; D013936:Thymidine