SAR by oxime-containing peptide libraries: application to Tsg101 ligand optimization.
HIV-1 viral assembly requires a direct interaction between a Pro-Thr-Ala-Pro ("PTAP") motif in the viral protein Gag-p6 and the cellular endosomal sorting factor Tsg101. In an effort to develop competitive inhibitors of this interaction, an SAR study was conducted based on the application of post solid-phase oxime formation involving the sequential insertion of aminooxy-containing residues within a nonamer parent peptide followed by reaction with libraries of aldehydes. Approximately 15-20-fold enhancement in binding affinity was achieved by this approach.
Liu
Fa
F
Laboratory of Medicinal Chemistry, CCR, NCI-Frederick, Building 376 Boyles Street, Frederick, MD 21702, USA.
Stephen
Andrew G
AG
Waheed
Abdul A
AA
Aman
M Javad
MJ
Freed
Eric O
EO
Fisher
Robert J
RJ
Burke
Terrence R
TR
D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D008024:Ligands; D010091:Oximes / Q000737:chemistry*; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism*; D000099177:Tsg101 Protein
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008024:Ligands; D010091:Oximes; D019151:Peptide Library; D010455:Peptides; D014157:Transcription Factors; D000099177:Tsg101 Protein