Lipid A, the lipid anchor portion of lipopolysaccharide (LPS or endotoxin) in the gram-negative bacterial outer membrane, exhibits variations in chemical structure that are responsible for the expression of pathophysiological effects. These variations occur in the phosphate and fatty acid components that modify the Lipid A backbone (two glucosamine molecules linked by a 1-6 b glycosidic bond). The diphosphoryl derivative has been shown to have a large tilt angle of the glucosamine backbone with respect to the membrane surface and a conical molecular shape (larger cross-section of the hydrophobic than the hydrophilic moiety). These attributes may partially account for the rather high endotoxicity of the compound. The monophosphoryl derivative on the other hand has a smaller tilt angle and a more cylindrical shape, and as a result is rather endotoxically inactive¹. Biological diversity of detoxified lipid A is exemplified by its multifunctional activities, including acting as an adjuvant², inducing tolerance to Salmonella enteritidis LPS and tumor necrosis factor alpha (TNF-alpha)³, attenuating platelet thrombosis⁴, and attenuating interoperative ventricular dysfunction "stunning" associated with aortic cross-clamping and reperfusion⁵.

Vaccines: Vaccine development is dependent on immunological adjuvants that mediate and promote a wide variety of immune responses. The immunological response to detoxified lipid A is dependent on the vehicle formulation. Either an aqueous vehicle or an oil-in water emulsion can be used to modulate the vaccine strategies being investigated today. DeBecker et. al. suggest that detoxified lipid A may induce an antigen-specific primary immune response by provoking the migration and maturation of dendritic cells that are the physiological adjuvant of the immune system¹.

Cardiac protection against ischaemia: Mechanisms involved with the cardioprotection are still unclear. A role for inducible nitric oxide synthase (iNOS) has been proposed and confirmed with the pharmacological inhibition and gene knockout mice⁶. Whereas Gyorgy et. al. suggest that NO acts as a trigger rather than a direct mediator of the delayed cardioprotective effect⁷.

1. Seydel, U., M. Oikawa, K. Fukase, S. Kusumoto, and K. Brandenburg. (2000). Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity. Eur J Biochem 267:3032-9.
2. De Becker, G., V. Moulin, B. Pajak, C. Bruck, M. Francotte, C. Thiriart, J. Urbain, and M. Moser. (2000). The adjuvant monophosphoryl lipid A increases the function of antigen- presenting cells. Int Immunol 12:807-815.
3. Wy, C.A., M. Goto, R.I. Young, T.F. Myers, and J. Muraskas. (2000). Prophylactic treatment of endotoxic shock with monophosphoryl lipid A in newborn rats. Biol Neonate 77:191-5.
4. Przyklenk, K., K. Hata, P. Whittaker, and G.T. Elliott. (2000). Monophosphoryl lipid A: a novel nitric oxide-mediated therapy to attenuate platelet thrombosis? J Cardiovasc Pharmacol 35:366-75.
5. Abd-Elfattah, A.S., J.H. Guo, S.P. Goa, G.A. Elliot, P. Weber, M.A. Mahgoub, R. Marktanner, and A. Mohamed. (1999). Myocardial protection with monophosphoryl lipid-A against aortic cross clamping-induced global stunning. Ann Thorac Surg 68:1954-9.
6. Xi, L., N.C. Jarrett, M.L. Hess, and R.C. Kukreja. (1999). Essential role of inducible nitric oxide synthase in monophosphoryl lipid A-induced late cardioprotection: evidence from pharmacological inhibition and gene knockout mice. Circulation 99:2157-63.
7. Gyorgy, K., B. Muller, A. Vegh, A.L. Kleschyov, and J.C. Stoclet. (1999). Triggering role of nitric oxide in the delayed protective effect of monophosphoryl lipid A in rat heart. Br J Pharmacol 127:1892-8.

• Adjuvants
• Monophosphoryl Lipid A (Synthetic) (PHAD™)
• 22:0 Trehalose (TDB)
• DDA / DDAB - Dimethyldioctadecylamonium Bromide