Inhibition of HIV-1 Protease by a Subunit of Didemnaketal A

Selective disruption of protein aggregation by cyclodextrin dimers

“…Other approaches to blocking protein-protein interactions have been reported recently (1,2,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29), many with peptides or peptide mimics. Our work suggests that the specific binding of hydrophobic side chains by CD dimers that we had reported earlier can be extended to proteins and that it is another way to block protein aggregation.…”

Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: A single mode of inhibition for the three HIV enzymes?

“…By fusing a non-catalytically active D25N HIV PR variant to the DNA-binding domain of the repressor protein from bacteriophage , a hybrid repressor was generated that allowed high-throughput screening of a library of 5 × 10 8 peptides with nine random amino acid residues. Less than one peptide in 10 6 was found to be able to disrupt HIV PR monomer association and in those identified there was an abundance of non-polar residues, especially valine, alanine, and glycine (Fan et al, 1998). Addition of a cysteine residue to the C-terminus of one of these peptides and crosslinking with the homobifunctional reagent 1,6-hexane-bis-vinylsulfone, led to a 40-fold more potent dissociative inhibitor (dissociative inhibition constant of 0.8 M) (Fig.…”

“…ursolic acid) identified through a pharmacophorebased computer search of the Cambridge Structural Database, and several simplified pentaester derivatives of didemnaketals A and B (first isolated from a marine ascidian belonging to the genus Didemnum) (Fan et al, 1998). Fig.…”

Lipopeptides as Dimerization Inhibitors of HIV-1 Protease

“…Since the active site is formed by both half-enzymes -which are connected by a ␤-sheet formed of the four intercalated terminal amino acid segments at the 'interface' (Wlodawer and Vondrasek, 1998), -reagents that interfere with formation or stability of the functional PR dimer can abolish activity by 'dimerization inhibition'. This mode of inhibition was observed for peptides with the N-or C-terminal amino acid sequences (Zhang et al, 1991, Schramm et al, 1991, and led to the identification of improved inhibitory peptides (Babé et al, 1992, Franciskovich et al, 1993, Uhliková et al, 1996, Zutshi et al, 1997, Fan et al, 1998Bouras et al, 1999) and to the formulation of a 'consensus sequence' Ile-Ser-Tyr-Glu-Leu (with possible conservative amino acid exchanges) for dimerization inhibitors (Schramm et al, 1996). This structure emphasizes the ␤-sheet characteristics of the inhibitory peptides, the value of two negative charges in positions 98 (Glu or Asp) and 99 (free C-terminus), the hydrophobic side chain in position 99 and, especially, the anchor residue Tyr in position 97 (using the sequence numbering of PR).…”