• combinatorial peptide libraries;
  • hexapeptide ligands;
  • low-abundance proteome;
  • mass spectrometry


The present review covers modern aspects of combinatorial peptide ligand libraries (CPLL), as used to analyze the “low-abundance proteome” in association with mass spectrometry. First, the capturing properties of baits of different lengths (from single amino acid to hexa-peptides) are described to show that a plateau is rapidly reached above a tetra-peptide in length, thus confirming the validity of having adopted hexapeptides for the considered application. The mechanism of interaction with proteins from very complex proteomes and the ability to decrease the dynamic concentration range is demonstrated with the help of mass spectrometry analysis. Examples are given on how treatment with CPLLs dramatically improves the detectability of peptides in mass spectrometry analysis, permitting detection of a very large number of proteins as compared with control, untreated samples. The use of complementary libraries is discussed with the aim to discover additional low-abundance species that escaped the first library. A discussion on the possibility to discover extremely rare gene products, and the quantitative aspect of the technology when associated with mass spectrometry is also provided. Some insights on the applications for hidden, low-abundance biomarkers are also presented. © 2008 Wiley Periodicals, Inc., Mass Spec Rev 27: 596–608, 2008