title: Design and synthesis of lipid-coupled inositol 1,2,3,4,5,6-hexakisphosphate derivatives exhibiting high-affinity binding for the HIV-1 MA domain.
abstract: The precursor of Gag protein (Pr55(Gag)) of human immunodeficiency virus, the principal structural component required for virus assembly, is known to bind d-myo-phosphatidylinositol 4,5-bisphosphate (PIP2). The N-terminus of Pr55(Gag), the MA domain, plays a critical role in the binding of Pr55(Gag) to the plasma membrane. Herein, we designed and synthesized myo-phosphatidylinositol 2,3,4,5,6-pentakisphosphate (PIP5) derivatives comprising highly phosphorylated inositol and variously modified diacylglycerol to examine the MA-binding properties. The inositol moiety was synthesized starting with myo-inositol and assembled with a hydrophobic glycerol moiety through a phosphate linkage. The Kd value for MA-binding of the PIP5 derivative 2 (Kd = 0.25 μM) was the lowest (i.e., highest affinity) of all derivatives, i.e., 70-fold lower than the Kd for the PIP2 derivative 1 (Kd = 16.9 μM) and 100-fold lower than the Kd for IP6 (Kd = 25.7 μM), suggesting the possibility that the PIP5 derivative blocks Pr55(Gag) membrane binding by competing with PIP2 in MA-binding.
authors.affiliation: Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. motsuka@gpo.kumamoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tateishi
authors.forename: Kensaku
authors.initials: K
authors.lastname: Anraku
authors.forename: Ryoko
authors.initials: R
authors.lastname: Koga
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Mikako
authors.initials: M
authors.lastname: Fujita
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
mesh_terms: D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D007295:Inositol Phosphates / Q000138:chemical synthesis* / Q000378:metabolism; D010833:Phytic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D011498:Protein Precursors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance
chemical_list: D007295:Inositol Phosphates; D011498:Protein Precursors; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D010833:Phytic Acid