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Peptoids: a modular approach to drug discovery
R J Simon1, R S Kania, R N Zuckermann
1Chiron Corporation, Emeryville, CA 94608.
Summary
Peptoids, N-substituted glycine oligomers, offer greater conformational diversity than peptides, enabling novel molecule library generation. These peptoid ligands show comparable affinities to peptide counterparts in biological systems.
Area of Science:
- Chemical Biology
- Organic Chemistry
- Biochemistry
Background:
- Peptoids, oligomers of N-substituted glycines, represent a versatile scaffold for creating diverse molecular libraries.
- Conformational analysis indicates peptoids possess a broader range of accessible states compared to traditional peptides.
Purpose of the Study:
- To explore the synthesis and properties of peptoid oligomers.
- To evaluate the potential of peptoids as peptide mimics in biological applications.
Main Methods:
- Peptoid monomers with t-butyl-based side-chains and Fmoc protection were synthesized.
- Controlled manual and robotic oligomerization utilized phosphonium-based activators, similar to peptide synthesis.
- Stability to enzymatic hydrolysis and binding affinities of peptoid ligands were assessed.
Main Results:
- A library of 15 peptoid monomers and 10 oligomers was synthesized.
- Peptoid conformers exhibit greater diversity than peptides, as shown by Ramachandran plots.
- Peptoid ligands demonstrated comparable binding affinities to peptide ligands for bovine pancreatic alpha-amylase, HAV 3C proteinase, and HIV TAR RNA.
Conclusions:
- Peptoids provide a chemically diverse platform for generating novel molecular entities.
- The conformational flexibility of peptoids enhances their utility in drug discovery and chemical biology.
- Peptoid-based libraries hold promise for receptor- and enzyme-based screening assays.