Peptoids: a modular approach to drug discovery.
Peptoids, oligomers of N-substituted glycines, are described as a motif for the generation of chemically diverse libraries of novel molecules. Ramachandran-type plots were calculated and indicate a greater diversity of conformational states available for peptoids than for peptides. The monomers incorporate t-butyl-based side-chain and 9-fluorenylmethoxy-carbonyl alpha-amine protection. The controlled oligomerization of the peptoid monomers was performed manually and robotically with in situ activation by either benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(pyrrolidino)phosphonium hexaflurophosphate. Other steps were identical to peptide synthesis using alpha-(9-fluorenylmethoxycarbonyl)amino acids. A total of 15 monomers and 10 oligomers (peptoids) are described. Preliminary data are presented on the stability of a representative oligopeptoid to enzymatic hydrolysis. Peptoid versions of peptide ligands of three biological systems (bovine pancreatic alpha-amylase, hepatitis A virus 3C proteinase, and human immunodeficiency virus transactivator-responsive element RNA) were found with affinities comparable to those of the corresponding peptides. The potential use of libraries of these compounds in receptor- or enzyme-based assays is discussed.
Simon
R J
RJ
Chiron Corporation, Emeryville, CA 94608.
Kania
R S
RS
Zuckermann
R N
RN
Huebner
V D
VD
Jewell
D A
DA
Banville
S
S
Ng
S
S
Wang
L
L
Rosenberg
S
S
Marlowe
C K
CK
D000478:Alkylation; D000595:Amino Acid Sequence; D002942:Circular Dichroism; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D007536:Isomerism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D034444:Peptoids; D017434:Protein Structure, Tertiary
D010455:Peptides; D034444:Peptoids; D005998:Glycine