title: Phenotypic screening of phylomer peptide libraries derived from genome fragments to identify and validate new targets and therapeutics.
abstract: BACKGROUND
  Phenotypic screening of random peptide libraries has been hampered by very poor hit rates. This is probably due to the fact that random combinatorial peptide libraries contain an insufficiently large proportion of secondary and/or tertiary structures that are likely to interact in a stable manner with multiple classes of potential target proteins. Phylomer libraries, by contrast, are derived from sequences of genomes that have been through millions to billions of years of evolution and were therefore hypothesized to be more likely to encode appropriate structures, which have been selected to stably bind with high affinity to protein surfaces. This approach is analogous to small-molecule libraries constructed to provide a rich source of structures (often found in natural products) that are common to the pharmacophores of known drugs.
  
  
  CONCLUSIONS
  Phenotypic screens of phylomer libraries show very high hit rates for bioactive peptides, suggesting that they may be a useful tool for target discovery and validation. Biophysical evidence suggests that this high activity may be due to the high proportion of affinities of unmodified peptides in the low nanomolar range.
  
  
  CONCLUSIONS
  The high hit rates from phylomer libraries are sufficient to allow libraries composed of synthetic peptides to be synthesized and screened in parallel high-throughput screening formats. In addition to allowing the identification of new targets, the phylomer peptides themselves may be useful as structural probes to map epitopes of target vulnerability and as leads in therapeutic discovery.
authors.affiliation: Centre for Child Health Research, University of Western Australia, Perth, WA, Australia 6010, Australia. paulw@phylogica.com
authors.forename: Paul M
authors.initials: PM
authors.lastname: Watt
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D015894:Genome, Human; D057166:High-Throughput Screening Assays; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D011108:Polymers / Q000737:chemistry; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019151:Peptide Library; D010455:Peptides; D011108:Polymers; D011506:Proteins