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

Iolanda Cuccovia,Cláudia Nunes,Daniela Lopes-de-Campos,Catarina Pereira-Leite,Philippe Fontaine,Salette Reis

doi:10.3390/molecules24030516

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.

Highlights

Drug discovery is primarily based on finding or designing new molecules to target a biomolecule in order to achieve a therapeutic benefit [1]
Langmuir isotherms showed that licofelone caused the expansion of the DPPC monolayer (Figure 2a)
This effect has been associated with an intercalation of the compound into the phospholipid monolayer [33] and/or an increase of the monolayer fluidity [34]

Summary

Introduction

Drug discovery is primarily based on finding or designing new molecules to target a biomolecule in order to achieve a therapeutic benefit [1]. Proteins are the main biological targets considered in the rational design of novel drugs. Other biomolecules have been gaining attention in the last decades, with the emergence of DNA and RNA-based gene therapy [2,3] and membrane lipid therapy [4]. Lipids were the last biomolecules to be considered as biological targets, for two main reasons: (a) the huge amount of different lipids found in the human body; and (b) powerful lipid profiling techniques, such as high-resolution mass spectrometry, were recently developed [5]. Cell membranes are nowadays considered as a complex, dynamic, and heterogeneous conjunction of lipids, proteins, and carbohydrates, functioning as platforms to control signal transduction.

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