Intriguing structure-activity relations underlie the potent inhibition of HIV protease by norstatine-based peptides

Conformational analysis of HIV-1 protease inhibitors: 2. Thioproline P1? Residue in the potent inhibitor KNI-272

“…Tam and coworkers have likewise shown a 400-fold reduction in potency for closely related norstatine-based inhibitors. 11 Our models suggest that if the P ᎐P X amide in epi-KNI-272 adopts a cis 1 1 conformation, it will be able to maintain multiple Ž . interactions with catalytic aspartates Fig.…”

“…This translates into approximately a 100-fold difference in binding, in good agreement with the experimental results on norstatine-based inhibitors from two different labs. 11,12 Another way to address the loss in potency of the epi isomer is to ask the following question: If the cis conformation is so much higher in energy, why does it not adopt a trans configuration? One reason, of course, is the loss of multiple hydrogen bonds with the catalytic aspartates.…”

“…This is opposite from that found in all other published HIV-PR inhibitor crystal structures. Tam et al 11 compared the binding of these two series of compounds and found that a com-Ž pound with norstatine core Z-Asn-Phe-…”

“…Changing the stereochemistry of the central hydroxyl group, or changing the P X 1 ring, can lead to large changes in binding potency. 11 Fourth, compounds such as 1᎐3 are interesting because, conceptually, they are reminiscent of the Phe᎐Pro dipeptide which occupies the P ᎐P X posi- 1 1 tion in several of the naturally occurring substrates for HIV-PR. One may speculate on the structural relationship between the P X substrate and the P X 1 1 ring substituent in these inhibitors.…”

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

“…Researchers from Syntex Research Canada independently synthesized compounds 97 and 98, and their derivatives, with similar inhibitory activities [175]. They also designed macrocyclic hydroxyamide peptidic inhibitors.…”