Application of ring-closing metathesis macrocyclization to the development of Tsg101-binding antagonists.
HIV-1 viral budding involves binding of the viral Gag(p6) protein to the ubiquitin E2 variant domain of the human tumor susceptibility gene 101 protein (Tsg101). Recognition of p6 by Tsg101 is mediated in part by a proline-rich motif that contains the sequence 'Pro-Thr-Ala-Pro' ('PTAP'). Using the p6-derived 9-mer sequence 'PEPTAPPEE', we had previously improved peptide binding affinity by employing N-alkylglycine ('peptoid') residues. The current study applies ring-closing metathesis macrocyclization strategies to Tsg101-binding peptide-peptoid hybrids as an approach to stabilize binding conformations and to observe the effects of such macrocyclization on Tsg101-binding affinity and bioavailability.
Liu
Fa
F
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health Frederick, MD 21702, United States. liuf@ncifcrf.gov
Stephen
Andrew G
AG
Waheed
Abdul A
AA
Freed
Eric O
EO
Fisher
Robert J
RJ
Burke
Terrence R
TR
D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism; D000099177:Tsg101 Protein
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D005456:Fluorescent Dyes; D047028:Macrocyclic Compounds; D010455:Peptides; D034444:Peptoids; D014157:Transcription Factors; D054301:gag Gene Products, Human Immunodeficiency Virus; D000099177:Tsg101 Protein