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\begin{document}

\title{Ticagrelor increases its own affinity to P2Y12 receptor by directly
changing the plasma membrane lipid order in platelets}



\author[1]{Kyrylo Pyrshev}%
\author[2]{Florentin Allemand}%
\author[2]{Vahideh Rabani}%
\author[3]{Semen Yesylevskyy}%
\author[2]{Siamak Davani}%
\author[2]{Christophe Ramseyer}%
\author[2]{Jennifer Lagoutte-Renosi}%
\affil[1]{Palladin Institute of Biochemistry National Academy of Sciences of Ukraine}%
\affil[2]{Franche-Comté University}%
\affil[3]{Institute of Physics National Academy of Sciences of Ukraine}%


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  \date{June 07, 2024}


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\begin{abstract}
Background and Purpose: Although the amphiphilic nature of the widely
used antithrombotic drug Ticagrelor is well known, it was never
considered as a membranotropic agent, which is able to interact with
lipid bilayer in a receptor-independent way. In this work we investigate
the influence of Ticagrelor on plasma membrane lipid order in platelets
and whether this could modulate affinity of P2Y12 receptor to
Ticagrelor. Experimental Approach: Here, we combined fluorescent in
situ, in vitro and in silico approaches to probe the interactions
between the plasma membrane of platelets and Ticagrelor. The influence
of Ticagrelor on the lipid order of the platelets' plasma membrane and
large unilamellar vesicles was studied using advanced fluorescent probe
NR12S. Further, the properties of the model lipid bilayers in presence
of Ticagrelor were characterized by molecular dynamics simulations.
Finally, the influence of an increased lipid order on the dose response
of platelets to Ticagrelor was studied. Key Results: Ticagrelor
incorporates spontaneously into lipid bilayers and affects the lipid
order of the membranes of model vesicles and isolated platelets in
non-trivial composition and concentration-dependent manner. We showed
that higher plasma membrane lipid order in platelets leads to the lower
IC50 for Ticagrelor. It is shown that membrane incorporation of
Ticagrelor increases the affinity of the drug to its own therapeutic
target, the P2Y12 receptor, by means of increasing the order of the
platelet's plasma membrane. Conclusion and Implications: A novel dual
mechanism of Ticagrelor action is suggested that combines direct binding
to P2Y12 receptor with simultaneous modulation of receptor's lipid
microenvironment.%
\end{abstract}%



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