Synthesis of Archaeal Bipolar Lipid Analogues:  A Way to Versatile Drug/Gene Delivery Systems

Abstract

A synthetic route for the preparation of symmetrical and unsymmetrical archaeal tetraether-like analogues has been described. The syntheses are based upon the elaboration of hemimacrocyclic tetraether lipid cores from versatile building blocks followed by simultaneous or sequential introduction of polar head groups. Functionalizations of the tetraether lipids with neutral lactose or phosphatidylcholine polar heads and cationic glycine betaine moieties were envisaged both to increase membrane stability and to exhibit interactions with charged nucleic acids. Additionally, mannose and lactose triantennary clusters designed as multivalent ligands for selective interaction with lectin-type receptors were also efficiently synthesized for active cell/tissue targeting.

Archaebacterial bipolar tetraether lipids: Physico-chemical and membrane properties

“…A number of acyclic, macrocyclic and hemimacrocyclic tetraether lipids have been synthesized (Benvegnu et al, , 2005Brard et al, 2004Brard et al, , 2007Eguchi et al, 1998;Kim and Thompson, 1992;Nakamura et al, 2007;Thompson et al, 1992) (for a recent review, see Benvegnu et al, 2008;Jacquemet et al, 2009). Synthetic methods have been developed to incorporate cyclopentane rings into the isoprenoid chain, diacetylenic groups into the polymethylene units, and various polar headgroups to the synthetic tetraether lipid cores Brard et al, 2004Brard et al, , 2007Eguchi et al, 1998;Patwardhan and Thompson, 2000) and to create varying alkyl chain lengths in the hydrocarbon core region (Nakamura et al, 2007).…”

“…Synthetic methods have been developed to incorporate cyclopentane rings into the isoprenoid chain, diacetylenic groups into the polymethylene units, and various polar headgroups to the synthetic tetraether lipid cores Brard et al, 2004Brard et al, , 2007Eguchi et al, 1998;Patwardhan and Thompson, 2000) and to create varying alkyl chain lengths in the hydrocarbon core region (Nakamura et al, 2007). However, none of the synthetic BTL (also known as bolaamphiphiles) is identical to the natural P2 or PLFE archaeal lipids containing cyclopentane rings.…”

“…The neutral hydroxyl or lactosyl groups in the synthetic BTL are efficient stabilizing agents in the presence of bile salt-like detergents; and, lactose and phosphatidylcholine moieties enhance stability towards serum lipoproteins (Benvegnu et al, 2005). Lactose and mannose conjugated archaeosomes could be recognized by asialoglycoprotein receptors and mannose receptors (Benvegnu et al, 2005;Brard et al, 2007). Via receptor-mediated endocytosis, archaeosomes can be taken up by cells (Sprott et al, 2003).…”

Archaeal Diversity and Their Biotechnological Potential

“…The isoprenoid glycerolipid membrane of archaeosomes can develop into a bilayer, a monolayer, or a combination of mono-and bilayers made from bipolar and monopolar archaeal lipids (Jacquemet et al, 2009). The archaeal lipids formulations have shown to exhibited relatively higher physico-chemical stabilities to oxidative stress, high temperature, alkaline pH, action of phospholipases, bile salts and serum media (Brard et al, 2007). These properties contribute to their efficacy as self-adjuvant vaccine delivery vesicles.…”

Nature as a source of inspiration for cationic lipid synthesis

“…Moreover, bipolar archaeal lipids span the membrane from one side to the other constituting a single-layer membrane with a higher degree of physical rigidity than bilayer membranes. These features have been applied to design archaeal bipolar lipid analogues for lipoplex mediated gene delivery (Benvegnu et al 2005;Brard et al 2007). The dicationic glycine betaine-based tetraether GRcat 10 ( Fig.…”