208169-69-1Relevant academic research and scientific papers
Macrocyclic inhibitors of penicillopepsin. 1. Design, synthesis, and evaluation of an inhibitor bridged between P1 and P3
Meyer, J. Hoyt,Bartlett, Paul A.
, p. 4600 - 4609 (1998)
The macrocyclic peptidyl phosphonate 1-L was designed on the basis of the conformation of an acyclic analogue (4) bound to the aspartic protease penicillopepsin. This material and the two acyclic comparison compounds 2-L and 3 were synthesized and evaluated as inhibitors; their binding affinity was found to be inversely related to the degree of conformational flexibility across the series: 3 (K(i) = 110 μM), 2- L (K(i) = 7.6 μM), 1-L (K(i) = 0.80 μM). NMR methods in conjunction with molecular modeling were used to assign the stereochemical configurations of the precursor 16-L and its diastereomer 16-D and to determine the solution conformations of the macrocyclic ring systems. The conformation of the peptide backbone in 1-L closely approximates that desired for a mimic of the lead inhibitor 4, and it appears that the low-energy conformation of 1-L can be accommodated in the pencillopepsin active site without significant distortion.
