Key result
NMR and in silico modeling demonstrated that losartan directly interacts with the hydrophobic region of the N-terminal Ig-like domain of GPVI, primarily via its phenyl group and tetrazole ring.
Losartan inhibits platelet aggregation by directly interacting with the hydrophobic region of the N-terminal Ig-like domain of GPVI, specifically via its phenyl group and tetrazole ring.
Losartan-GPVI interaction in animals may inform antiplatelet strategies; leaves open clinical translation and human confirmation.
GPVI is a key receptor for collagen-induced platelet activation. Loss or inhibition of GPVI causes only mildly prolonged bleeding times but prevents arterial thrombus formation in animal models. Therefore, GPVI is considered to be a potent target molecule for therapy of thrombotic diseases. Recently, it was reported that the AT(1)-receptor antagonist losartan (DuP-753) and EXP3179 inhibit platelet adhesion and aggregation via GPVI. However, it is still not clear how losartan is associated with inhibition of binding between GPVI and collagen at the molecular level. Here, we show by NMR that losartan directly interacts with the hydrophobic region consisting of strands C' and E in the N-terminal Ig-like domain of GPVI. A reliable GPVI-losartan complex model is presented by using a combination of NMR data and in silico tools. These data indicated that the phenyl group with the tetrazole ring in losartan plays a crucial role in the interaction with GPVI.
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Ono et al. (2010) studied this question. Losartan (DuP-753) was evaluated on Interaction between losartan and GPVI. NMR and in silico modeling demonstrated that losartan directly interacts with the hydrophobic region of the N-terminal Ig-like domain of GPVI, primarily via its phenyl group and tetrazole ring.
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