Phosphatidylinositol inhibits microtubule assembly by binding to microtubule-associated protein 2 at a single, specific, high-affinity site.

The effects of various anionic phospholipids on the in vitro assembly of MAP2/tubulin microtubules has been examined. We show that the potency to inhibit is related to the polarity of the phospholipids and that this is consistent with a mode of action involving the sequencing of microtubule-associated proteins (MAPs) by nonspecific electrostatic interactions. The inhibitory potency of phosphatidylinositol (PI) is, however, considerably larger than predicted by this model. The effects of PI on MAP2/tubulin microtubule assembly have therefore been examined in greater detail by preparing phosphatidylcholine (PC) liposomes doped with increasing amounts of PI. We show that when the PI is sufficiently dispersed by dilution with PC, it inhibits microtubule assembly by binding to MAP2 with an apparent stoichiometry, after correction for the bilamellar nature of the liposomes, of 1:1 mol.mol-1 PI:MAP2. Furthermore, we show that the Kd of this interaction is in the submicromolar range.     

Identification and design of a novel series of MGAT2 inhibitors

[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to na?ve, p <0.01) in plasma triacylglycerol (TAG) concentration.     

Mouse monoclonal antibodies can nonspecifically inhibit the proliferation of human T-cell growth factor-dependent T cells

A large series of mouse monoclonal antibodies was found to inhibit the proliferation of T-cell growth factor (TCGF)-dependent human T-cell blasts as measured by the incorporation of tritiated thymidine. The specificity of the antibody appeared to be irrelevant for inhibition and two T-cell-specific antibodies did not prevent the absorption of TCGF by treated T cells. It is suggested that the antibodies function by the indirect release of suppressor factors by Fc receptor-bearing TCGF-dependent cells.