Solid-phase combinatorial library of norstatine-type isosters by the nitroaldol reaction.
A combinatorial library of norstatine-type peptide isosters as putative inhibitors of aspartic proteases is presented. The library was synthesized using a split-and-mix strategy designed to afford a one-bead-two-compounds library with the isosteric elements positioned centrally in peptide chains. Application of ladder synthesis during library generation enabled structure identification by MALDI-TOF mass spectroscopy. The library was screened against aspartic protease renin, and two types of inhibitors were identified, that is, XXX-psi[CHRCHOH)-XXX and an aldehyde arising from unreacted starting material. Selected hits were resynthesized and assayed in solution, revealing inhibitors of nanomolar potency.
Willert
Marianne
M
Department of Chemistry, Carlsberg Laboratory, Gamle Carlsbergvej 10, DK-2500 Valby, Denmark.
Benito
Juan M
JM
Meldal
Morten
M
D000596:Amino Acids / Q000737:chemistry; D000614:Aminocaproates / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D003432:Cross-Linking Reagents; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007700:Kinetics; D009574:Nitro Compounds / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D012083:Renin / Q000737:chemistry; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000596:Amino Acids; D000614:Aminocaproates; D003432:Cross-Linking Reagents; D007202:Indicators and Reagents; D009574:Nitro Compounds; D019151:Peptide Library; D010455:Peptides; C034495:3-amino-2-hydroxy-5-methylhexanoic acid; D012083:Renin