Tritiated D-ala1-peptide T binding: A pharmacologic basis for the design of drugs which inhibit HIV receptor binding

Autor: Paola Sacerdote, Patricia Williams, Michael R. Ruff, Candace B. Pert, Esther M. Sternberg, Paul L. Hallberg, Brian M. Martin, Craig C. Smith
Rok vydání: 1988
Předmět:
Zdroj: Drug Development Research. 15:371-379
ISSN: 1098-2299
0272-4391
DOI: 10.1002/ddr.430150404
Popis: The HIV virus initiates its infectious cycle through a high-affinity binding interaction between the envelope protein gp 120 and its receptor, the T4 (or CD4) molecule. An octapeptide sequence, termed peptide T, present in the second variable region of gp 120 from the ARV isolate, has been implicated as the attachement site. The core peptide required for activity has been further refined to a pentapeptide, and homologous pentapeptides are similarly positioned in 21 other sequenced HIV isolates. Utilizing a novel direct binding assay of 3H-D-ala1-peptide T, we now report that synthetic peptides derived from these other isolates are potent competitors of peptide T binding to T4-positive lymphocytes and brain membranes. Direct peptide T binding is also competable by purified virion gp 120, indicating that these ligands are interactive at the same receptor. Peptide T has sequence relatedness to the peptide vasoactive intestinal peptide (VIP), and VIP and its relevant homologous pentapeptide, VIP[7–11], are also potent inhibitors of peptide T binding. To determine the essential structural features responsible for receptor activity we have studied a series of synthetic peptides substituted with single D-amino acid residues. These data reveal that the tyrosine of position 7 in peptide T, present in all natural viral isolates, is obligate for receptor activity. Structure/function analysis for a large number of analogs is presented. Significantly, this binding assay is highly correlated with peptide bioactivity in several independent systems, indicating that this methodology can be used for rapid screening of novel, potential anti-AIDS therapeutics whose target is inhibition of virus gpl20 binding.
Databáze: OpenAIRE
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