title: Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation.
abstract: Protein-protein interactions are of critical importance in biological systems, and small molecule modulators of such protein recognition and intervention processes are of particular interest. To investigate this area of research, we have synthesized small-molecule libraries that can disrupt a number of biologically relevant protein-protein interactions. These library members are designed upon planar motif, appended with a variety of chemical functions, which we have termed "credit-card" structures. From two of our "credit-card" libraries, a series of molecules were uncovered which act as inhibitors against the HIV-1 gp41 fusogenic 6-helix bundle core formation, viral antigen p24 formation, and cell-cell fusion at low micromolar concentrations. From the high-throughput screening assays we utilized, a selective index (SI) value of 4.2 was uncovered for compound 2261, which bodes well for future structure activity investigations and the design of more potent gp41 inhibitors.
authors.affiliation: Department of Chemistry and Immunology and The Skaggs Institute for Chemical Biology and Worm Institute for Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Jack P
authors.initials: JP
authors.lastname: Kennedy
authors.forename: Xuxia
authors.initials: X
authors.lastname: Yan
authors.forename: Laura A
authors.initials: LA
authors.lastname: McAllister
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Jason A
authors.initials: JA
authors.lastname: Moss
authors.forename: Grant E
authors.initials: GE
authors.lastname: Boldt
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects* / Q000502:physiology; D008969:Molecular Sequence Data; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors