Licofelone-DPPC Interactions: Putting Membrane Lipids on the Radar of Drug Development

Abstract

(1) Background: Membrane lipids have been disregarded in drug development throughout the years. Recently, they gained attention in drug design as targets, but they are still disregarded in the latter stages. Thus, this study aims to highlight the relevance of considering membrane lipids in the preclinical phase of drug development. (2) Methods: The interactions of a drug candidate for clinical use (licofelone) with a membrane model system made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were evaluated by combining Langmuir isotherms, Brewster angle microscopy (BAM), polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS), and grazing-incidence X-ray diffraction (GIXD) measurements. (3) Results: Licofelone caused the expansion of the DPPC isotherm without changing the lipid phase transition profile. Moreover, licofelone induced the reduction of DPPC packing density, while increasing the local order of the DPPC acyl chains. (4) Conclusions: The licofelone-induced alterations in the structural organization of phosphatidylcholine monolayers may be related to its pharmacological actions. Thus, the combination of studying drug-membrane interactions with the pharmacological characterization that occurs in the preclinical stage may gather additional information about the mechanisms of action and toxicity of drug candidates. Ultimately, the addition of this innovative step shall improve the success rate of drug development.

Subtle chemical modification for enrichment of Fmoc-amino acid at a phospholipid interface

“…Given that the Fmoc group was the source of the UV-vis reection signal, the amount of the Fmoc-Y and Fmoc-F molecules at the mixed monolayer could be directly compared. 36 An intercrossing in the integral value of the UV-vis reection spectra for the DMPA : Fmoc-F and DMPA : Fmoc-Y monolayers was found at ca. 0.7 nm 2 per DMPA molecule.…”

Phosphatidylcholine bilayers trigger the degradation of licofelone

“…These studies are particularly relevant for anti-inflammatory drugs as their efficacy and toxicity seem to be directly related to the drugs interaction with membrane lipids and proteins (11,14,21). Despite the information collected in the last decades, studies on drug-membrane interactions are often disregarded in drug discovery but they seem to be a promising strategy to improve the success rate of this laborious process, as previously suggested elsewhere (22,23).…”

“…Apesar da informação recolhida nas últimas décadas, os estudos de interação fármaco-membrana são ainda regularmente desconsiderados durante o desenvolvimento de novos fármacos. No entanto, estes parecem constituir uma estratégia interessante a adotar para melhorar a taxa de sucesso deste longo processo, tal como se sugeriu anteriormente (22,23). Neste contexto, este trabalho tem como objetivo avaliar as interações de um fármaco em desenvolvimento (licofelone) com um modelo de membrana constituído por uma fosfatidilcolina (DMPC).…”

Membrane Interactivity of Non-steroidal Anti-inflammatory Drugs: A Literature Review

“…Such speculative enzyme inhibition may be supported by the dual inhibitory effects of anti-inflammatory licofelone on COX and 5-LOX [77]. Licofelone modifies the structural organization of DPPC membranes [78] and decreases the fluidity of cellular membranes [26].…”

“…Bioactive compounds to decrease membrane fluidity and permeability can induce apoptosis in human breast cancer cells [107] and colon cancer cells [108]. While licofelone triggers apoptosis in human colon cancer cells independently from inhibition of COX and 5-LOX [109], this NSAID interacts with DPPC membranes [110]. Licofelone also inhibits the epidermal growth factor receptor signaling to induce the apoptosis of colon cancer cells by decreasing the fluidity of cellular membranes [26].…”