Phylomers are peptides derived from fragments of proteins encoded by biodiverse genomes. Phylomer libraries were devised as a strategy to enable screening of a diverse array of peptides representing sequences that form secondary and super-secondary structures within natural proteins, some of which have evolved to bind to protein interfaces. By screening biodiverse peptide libraries, we aim to overcome poor hit rates in phenotypic and target-directed screens of random peptide libraries, presumed to be due to the limited structural complexity that can be assumed by the random amino acid composition of these peptides. Consistent with this strategy, we present evidence that Phylomer libraries derived from biodiverse genomes do offer a rich source of high-quality hits in both target-directed and phenotypic screens. We present a bioinformatic analysis of Phylomer peptide libraries and empirical data from representative case studies of Phylomer library screens. Taken together, these data illustrate the utility of this alternative approach to identify peptide hits of high quantity and quality, both for therapeutic applications and as probes for target identification and validation.
