Inhibitors of the protease from human immunodeficiency virus: synthesis, enzyme inhibition, and antiviral activity of a series of compounds containing the dihydroxyethylene transition-state isostere

Abstract

A number of potential HIV protease inhibitory peptides that contain the dihydroxyethylene isostere were prepared and evaluated for their enzyme binding affinity and antiviral activity in cell cultures. From the template of a previously reported active peptide A, modifications at the N-and C-terminal groups were assessed for potential maintenance of good inhibitory activity of the resulting peptides. Among the active peptides found, peptide XVIII exhibited potent enzyme inhibitory activity. Interestingly, the previously reported, effective l(S)-amino-2(i?)-hydroxyindan C-terminal group for the preparation of very active HIV protease inhibitory peptides could not be applied to the template of peptide XVIII. Molecular modeling of peptide XVIII was studied using the X-ray crystal structure of peptide A as a starting point in order to study the likely conformation of peptide XVIII in the active-site cleft. Relative binding conformations of peptide A and XVIII were obtained, although the reason for poor binding affinity for a number of congeneric peptides in this report was not straightforwardly apparent. More importantly, however, peptide XVIII was found to exhibit more effective antiviral activity in the HIV-l/PBMC assay than the reference peptide A which was previously reported to be approximately equal in efficacy to the reverse transcriptase inhibitor AZT in this assay.

Inhibitors of Human Immunodeficiency Virus Type 1 Protease Containing 2-Aminobenzyl-Substituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Activity, and Oral Bioavailability

“…Incorporation of AHI 10 in place of the P2‘ benzylamino moiety led to inhibitor 7 with 40-fold increased potency relative to 9 . AHI had been described previously as an effective surrogate for the P2‘ amino acid in HIV PR inhibitors containing a hydroxyethylene isostere 10 but was not beneficial in other inhibitors …”

Design, asymmetric synthesis, and evaluation of pseudosymmetric sulfoximine inhibitors against HIV-1 protease

“…The L-valine N-methylamide has been previously reported to improve ligand binding to the S 2 =S 2 0 pockets of the HIV-1 protease. 22 It has been featured in various peptidomimetic HIV-1 PI's with different TSMs to maintain a high degree of enzymatic inhibition activities. 23 Therefore, we incorporated the L-valine N-methylamide substituent into the pseudosymmetric sulfide core structure 17 to construct the corresponding peptidomimetic inhibitor 21.…”

“…4.1.15. Bis-[N-(2,2-dimethyl-8,8a-dihydro-3aH-indeno[(1S,2R)-1,2]-oxazol-3-yl) 2R-benzyl-3-yl propianamide] sulfoximine(22) …”

Transport characteristics of peptides and peptidomimetics: I. N‐methylated peptides as substrates for the oligopeptide transporter and P‐glycoprotein in the intestinal mucosa

“…This strategy often involves the replacement of a metabolically labile peptide bond with a peptide bond bioisostere, e.g. hydroxyethylamine (3), hydroxyethylene (7), dihydroxyethylene (8), aminimide (9) or pyrrolinone (10). An effective ‘minimalist’ approach to accomplish this objective involves N ‐methylation of a metabolically labile peptide bond (11,12).…”