Boosting of retinol activity using novel lecithin: Retinol acyltransferase inhibitors

Lecithin:retinol acyltransferase (LRAT) is the main enzyme catalysing the esterification of retinol to retinyl esters and, hence, is of central importance for retinol homeostasis. As retinol, by its metabolite retinoic acid, stimulates fibroblasts to synthesize collagen fibres and inhibits collagen-degrading enzymes, the inhibition of LRAT presents an intriguing strategy for anti-ageing ingredients by increasing the available retinol in the skin. Here, we synthesized several derivatives mimicking natural lecithin substrates as potential LRAT inhibitors. By exploring various chemical modifications of the core scaffold consisting of a central amino acid and an N-terminal acylsulfone, we explored 10 different compounds in a biochemical assay, resulting in two compounds with IC50 values of 21.1 and 32.7 mu M (compounds 1 and 2), along with a simpler arginine derivative with comparative inhibitory potency. Supported by computational methods, we investigated their structure-activity relationship, resulting in the identification of several structural features associated with high inhibition of LRAT. Ultimately, we conducted an ex vivo study with human skin, demonstrating an increase of collagen III associated with a reduction of the skin ageing process. In conclusion, the reported compounds offer a promising approach to boost retinol abundance in human skin and might present a new generation of anti-ageing ingredients for cosmetic application. La l & eacute;cithine/r & eacute;tinol acyltransf & eacute;rase (LRAT) est la principale enzyme qui catalyse l'est & eacute;rification du r & eacute;tinol en esters de r & eacute;tinyle et, par cons & eacute;quent, est d'une importance centrale pour l'hom & eacute;ostasie du r & eacute;tinol. & Eacute;tant donn & eacute; que le r & eacute;tinol, par son m & eacute;tabolite l'acide r & eacute;tino & iuml;que, stimule les fibroblastes pour synth & eacute;tiser les fibres de collag & egrave;ne et inhibe les enzymes de d & eacute;gradation du collag & egrave;ne, l'inhibition de la LRAT constitue une strat & eacute;gie int & eacute;ressante pour les ingr & eacute;dients anti-& acirc;ge en augmentant le r & eacute;tinol disponible dans la peau. Ici, nous avons synth & eacute;tis & eacute; plusieurs d & eacute;riv & eacute;s imitant les substrats naturels de la l & eacute;cithine comme inhibiteurs de LRAT potentiels. En & eacute;tudiant diff & eacute;rentes modifications chimiques du noyau compos & eacute; d'un acide amin & eacute; central et d'un acylsulfone N-terminal, nous avons & eacute;tudi & eacute; dix compos & eacute;s diff & eacute;rents dans le cadre d'un essai biochimique; il en est r & eacute;sult & eacute; deux compos & eacute;s avec des valeurs de CI50 de 21.1 et 32.7 mu m (compos & eacute;s 1 et 2), ainsi qu'un d & eacute;riv & eacute; d'arginine plus simple avec une puissance inhibitrice comparative. Avec le soutien de m & eacute;thodes computationnelles, nous avons & eacute;tudi & eacute; leur relation structure-activit & eacute;, ce qui a permis d'identifier plusieurs caract & eacute;ristiques structurelles associ & eacute;es & agrave; une inhibition & eacute;lev & eacute;e de la LRAT. Enfin, nous avons men & eacute; une & eacute;tude ex vivo sur la peau humaine, d & eacute;montrant une augmentation du collag & egrave;ne III associ & eacute;e & agrave; une r & eacute;duction du processus de vieillissement de la peau. En conclusion, les compos & eacute;s rapport & eacute;s offrent une approche prometteuse pour stimuler l'abondance du r & eacute;tinol dans la peau humaine et pourraient aboutir & agrave; une nouvelle g & eacute;n & eacute;ration d'ingr & eacute;dients anti-& acirc;ge pour des applications cosm & eacute;tiques. The inhibition of LRAT presents a strategy for increasing the available retinol/retinoic acid in the skin. We synthesized LRAT inhibitors mimicking natural lecithin substrates and supported by computational methods, we investigated their structure-activity relationship. In ex vivo studies with human skin we demonstrated proof of concept by increased collagen III.image