Lysis of membrane lipids promoted by small organic molecules: Reactivity depends on structure but not lipophilicity

Abstract

Several organic molecules of low molecular weight (<150 Da) are demonstrated to have substantial membrane-lytic potential despite having a low predicted lipophilicity (logD < 1 at neutral pH). In aqueous liposome dispersions, 38 aromatic compounds were tested for their ability to either promote lipid hydrolysis or directly participate in chemical reactions with lipid molecules. Behaviors observed included acyl transfer from the lipid to form a lipidated compound, both with and without concomitant lysolipid formation; increases in the rate of lipid hydrolysis without lipidation; and no reactivity. The variation in activity, including a notably higher activity for heterocycles such as amino-substituted benzimidazoles and indazoles, demonstrates the potential to predict or “design-in” lytic activity once the rules that govern reactivity are better understood. The nature of this chemical instability has significant ramifications for the use or presence of lipids in diverse fields such as materials chemistry, food chemistry, and cell physiology.

The association of lipids with amyloid fibrils

“…However, different results were obtained with total brain lipid extract, which serves to highlight that the outcome of many experiments in vitro is highly dependent on the experimental conditions. The presence of isotropic 31 P peaks in Aβ preparations studied by ssNMR has been noted on other occasions however ( 73 , 74 , 75 ) and may be a common feature in many model systems reflecting a detergent-like activity of the peptide or the formation of lysolipids by lytic processes involving the peptide ( 35 , 76 ).…”

Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection

“…In addition to passive diffusion, protonated molecules may also cross the phospholipid bilayer via a mechanism specific to this ion class involving degradation of the phospholipid fabric of the membrane . In contrast to passive diffusion, this degradative transport mechanism appears to be structure-dependent, rather than being governed by lipophilicity . Overall, achieving permeability for strong bases with high molecular weights is expected to be challenging.…”

A lipid nanoparticle platform for mRNA delivery through repurposing of cationic amphiphilic drugs

“…It is hypothesized that the typical physicochemical features of CADs and their known tendency to insert in lipid membranes would allow their incorporation into LNPs for mRNA complexation, thus replacing potentially harmful synthetic cationic lipids. Moreover, CADs have been described to modify lipid bilayer properties, which could promote RNA delivery efficiency [ [37] , [38] , [39] , [40] ]. Finally, incorporating both CADs and mRNA into LNPs should enable to merge the therapeutic activities of both drugs in a single formulation [ 41 ].…”