Synthesis and Screening of “One-Bead One-Compound” Combinatorial Peptide Libraries

In the “one-bead one-compound” (OBOC) combinatorial library method, compound beads are prepared by a “split-mix” synthesis approach that results in the display of many copies of the same compound on one single bead. This chapter focuses on the methods used for preparing peptide libraries, and the various screening methods that can be applied to both peptide and small molecule libraries. TentaGel resin is a good choice for OBOC peptide libraries due to its uniformity in size as well as its nonstickiness. This resin can be swollen in a wide range of solvents from water to toluene. In principle, either the Fmoc/t-But (9-fluorenylmethoxycarbonyl/tertbutyl) or t-Boc/Bn (tert-butyloxycarbonyl/benzyl) amino acid protection strategies could be used for library synthesis on TentaGel. The chapter also describes the procedure that uses N,N’-diisopropylcarbodiimide (DIC) as an activating reagent and 1-hydroxybenzotriazole (HOBt) as an additive to synthesize peptide libraries. Regarding the OBOC combinatorial libraries screening, tens of thousands to millions of compound beads are first mixed with a target molecule. The beads that interact with the target molecule will be identified and then isolated for structure determination. The enzyme-linked colorimetric assay screening method is discussed that can be used to screen both peptide and small molecule OBOC libraries.