Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides.
Incorporation of amino lactams into biologically active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection strategy has been developed for the systematic synthesis of peptides containing configurationally defined alpha- and beta-amino gamma-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates 9 and 8 minimized bis-alkylation and provided N-alkyl peptides, which underwent lactam annulation under microwave heating. Employing this solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 lactam derivatives and validated the effectiveness of this approach on peptides bearing aliphatic, aromatic, branched, charged, and heteroatomic side chains. The binding affinity IC(50) values of the GHRP-6 lactam analogues on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogues. In these cases, lactam analogues were prepared exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biological activity.
Jamieson
Andrew G
AG
Chemistry Department, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, Quebec H3C 3J7, Canada.
Boutard
Nicolas
N
Beauregard
Kim
K
Bodas
Mandar S
MS
Ong
Huy
H
Quiniou
Christiane
C
Chemtob
Sylvain
S
Lubell
William D
WD
D000596:Amino Acids / Q000737:chemistry; D005449:Fluorenes / Q000737:chemistry; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D017472:Receptors, Interleukin-1 / Q000737:chemistry; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry
D000596:Amino Acids; D005449:Fluorenes; D007769:Lactams; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D009842:Oligopeptides; D010455:Peptides; D017472:Receptors, Interleukin-1; D013449:Sulfonamides; C041048:growth hormone releasing hexapeptide