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

    Year: 2019

    Journal: Molecules, Volume 24, 1-Feb

    Authors: Pereira-Leite, Catarina; Lopes-de-Campos, Daniela; Fontaine, Philippe; Cuccovia, Iolanda M.; Nunes, Claudia; Reis, Salette

    Organizations: FCT (Fundacao para a Ciencia e a Tecnologia)Portuguese Foundation for Science and Technology [SFRH/BD/109621/2015]; POCH (Programa Operacional Capital Humano) [PD/BD/105957/2014]; EU (European Union)European Union (EU) [IF/00293/2015]; CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)National Council for Scientific and Technological Development (CNPq) [160446/2013-9, 301250/2013-8]; FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/08166-5]; INCT-FCx; EU [FEDER funds]European Union (EU) [POCI/01/0145/FEDER/007265]; FCT/MEC (Fundacao para a Ciencia e a Tecnologia and Ministerio da Educacao e Ciencia) [PT2020 UID/QUI/50006/2013]; CALIPSO [20130142]

    Keywords: lipid monolayers; DPPC; licofelone; langmuir isotherms; BAM; PM-IRRAS; GIXD

    (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.
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