Chemogenomics with peptide secondary structure mimetics.
There is increasing evidence that redox regulation of transcription, particularly activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB), is important in inflammatory diseases. Human thioredoxin (TRX), a member of the oxidoreductase superfamily, was initially identified, as a factor which augments the production of interleukin-2 receptor alpha (IL-2R alpha) in human T-cell lymphotropic virus type 1 (HTLV-1) infected patient T-cells. Substrates for the redox activity of TRX bind the active site cleft in extended strand structure. The rapid generation of high numbers of peptide secondary structure mimetics through solid-phase synthesis is a key technology for the identification of pharmaceutical leads based on such protein-peptide interactions. In this manuscript, we describe a chemogenomic approach utilizing an extended strand templated library to develop small molecule inhibitors to validate oxidoreductase molecular targets in a murine asthma model.
Eguchi
Masakatsu
M
Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
McMillan
Michael
M
Nguyen
Cu
C
Teo
Jia-Ling
JL
Chi
Emil Y
EY
Henderson
William R
WR
Kahn
Michael
M
D000818:Animals; D001249:Asthma / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors; D006801:Humans; D051379:Mice; D018716:Molecular Mimicry; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D019151:Peptide Library; D010455:Peptides; D043562:Receptors, G-Protein-Coupled