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.