An unusual functional group interaction and its potential to reproduce steric and electrostatic features of the transition states of peptidolysis.
The donor-acceptor interaction between a tertiary amine and an aldehyde, first observed among a select class of alkaloids, was deliberately established in a peptidomimetic (1a-c) to mimic features of the two principal transition states of peptide hydrolysis. Compounds 1a-c show preferential adoption in methanol and water of a 'folded' conformation displaying the interaction. Proportions of the folded form in MeOH range from 45% to 70% and can reach 84% in buffer. Significantly, three tendencies for the folded/unfolded equilibrium are observed: increasing solubility and polarity of the medium and decreasing temperature results in a higher extent of folding. In the absence of any parameter set available for this weak bond, no modeling studies were conducted to aid in the design of 1a-c. The successful straightforward synthesis of 1 and its folding and inhibition results with HIV-1 peptidase using FRET technology encourage studies to further pre-organize candidate molecules and to screen the structure space by modeling and parallel combinatorial chemistry.
Gautier
Arnaud
A
Laboratoire de Chimie, UMR 5182 ENS/CNRS, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, 69364 Lyon cedex 07, France.
Pitrat
Delphine
D
Hasserodt
Jens
J
D000447:Aldehydes / Q000737:chemistry*; D000588:Amines / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006860:Hydrogen Bonding; D006868:Hydrolysis; D007700:Kinetics; D008968:Molecular Conformation; D010447:Peptide Hydrolases / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017510:Protein Folding; D012995:Solubility; D055672:Static Electricity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature
D000447:Aldehydes; D000588:Amines; D010455:Peptides; D010447:Peptide Hydrolases