Design and synthesis of lipid-coupled inositol 1,2,3,4,5,6-hexakisphosphate derivatives exhibiting high-affinity binding for the HIV-1 MA domainElectronic supplementary information (ESI) available. See DOI: 10.1039/c4ob00350k

• Main Authors: Tateishi, Hiroshi, Anraku, Kensaku, Koga, Ryoko, Okamoto, Yoshinari, Fujita, Mikako, Otsuka, Masami
• Format: Journal Article
• Language: English
• Published: 18.06.2014
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c4ob00350k

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 (PIP 2 ). 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 (PIP 5 ) 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 K d value for MA-binding of the PIP 5 derivative 2 ( K d = 0.25 M) was the lowest ( i.e. , highest affinity) of all derivatives, i.e. , 70-fold lower than the K d for the PIP 2 derivative 1 ( K d = 16.9 M) and 100-fold lower than the K d for IP 6 ( K d = 25.7 M), suggesting the possibility that the PIP 5 derivative blocks Pr55 Gag membrane binding by competing with PIP 2 in MA-binding. Lipid-coupled inositol 1,2,3,4,5,6-hexakisphosphate binds to HIV-1 MA tightly through both electrostatic and hydrophobic interactions.